A Phase II Study With a Safety lead-in of Nivolumab in Combination With Bevacizumab or in Combination With Bevacizumab and Rucaparib for the Treatment of Relapsed Epithelial Ovarian, Fallopian Tube or Peritoneal Cancer
Phase: PHASE2
Conditions: Peritoneal Cancer, Ovarian Cancer, Fallopian Tube Cancer
Sponsor: Dana-Farber Cancer Institute



DF/HCC Protocol #: 16-263
Protocol Version Date: August 14, 2023
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SCHEMA (COHORT 1)
1 cycle = 14 days
Main Study:
Determine whether 
participant meets 
eligibility criteria
Treat with nivolumab 
and bevacizumab every 
14 days
Image every four cycles 
to determine response
Complete Response, 
Partial Response, or 
Stable Disease
Continue treatment with 
nivolumab and 
bevacizumab every 14 
days
Progressive Disease
Discontinue treatment 
unless participant meets 
criteria for treatment 
beyond disease 
progression
Safety Lead-In:
Enroll six participants 
who meet eligibility 
criteria
Treat with nivolumab and 
bevacizumab every 14 
days
Assess dose-limiting-
toxicities after participants 
have completed first two 
cycles
If regimen is deemed safe, 
proceed with further 
accrual in main study

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SCHEMA (COHORT 2)
1 cycle = 14 days
Main Study:
Determine whether 
participant meets 
eligibility criteria
Treat with nivolumab 
and bevacizumab every 
14 days and rucaparib 
twice daily continuous 
dosing
Image every four cycles to 
determine response
Complete Response, 
Partial Response, or 
Stable Disease
Continue treatment with 
nivolumab and 
bevacizumab every 14 
days and rucaparib 
twice daily continuous 
every 14 days dosing
Progressive Disease
Discontinue treatment 
unless participant meets 
criteria for treatment 
beyond disease 
progression
Safety Lead-In:
Enroll six participants 
who meet eligibility 
criteria
Treat with nivolumab and 
bevacizumab every 14 
days and rucaparib twice 
daily continuous dosing
Assess dose-limiting-
toxicities after participants 
have completed first four 
cycles (8 weeks)
If regimen is deemed safe, 
proceed with further 
accrual in main study

DF/HCC Protocol #: 16-263
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SCHEMA (COHORT 3)
1 cycle = 14 days
Main Study:
Determine whether 
participant meets 
eligibility criteria
Treat with nivolumab 
and bevacizumab every 
14 days and rucaparib 
twice daily continuous 
dosing
Image every four cycles 
to determine response
Complete Response, 
Partial Response, or 
Stable Disease
Continue treatment with 
nivolumab and 
bevacizumab every 14 
days and rucaparib 
twice daily continuous 
every 14 days dosing
Progressive Disease
Discontinue treatment 
unless participant meets 
criteria for treatment 
beyond disease 
progression

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TABLE OF CONTENTS
SCHEMA (COHORT 1)..................................................................................................................2
SCHEMA (COHORT 2)..................................................................................................................3
SCHEMA (COHORT 3)..................................................................................................................4
1.
OBJECTIVES......................................................................................................................8
1.1
Study Design............................................................................................................8
1.2
Primary Objectives...................................................................................................8
1.3
Secondary Objectives...............................................................................................8
1.4
Exploratory Objectives ............................................................................................9
2.
BACKGROUND .................................................................................................................9
2.1
Ovarian Cancer ........................................................................................................9
2.2
PD-1 Blockade as Immunotherapy in Oncology .....................................................9
2.3
PARP inhibitors in ovarian cancer.........................................................................10
2.4
IND Agents............................................................................................................11
2.5
Study Rationale......................................................................................................23
2.6
Rationale for Cohort 3 ...........................................................................................24
2.7
Correlative Studies Background ............................................................................25
3.
PARTICIPANT SELECTION...........................................................................................27
3.1
Eligibility Criteria..................................................................................................27
3.2
Exclusion Criteria ..................................................................................................29
3.3
Inclusion of Women and Minorities ......................................................................32
4.
REGISTRATION PROCEDURES ...................................................................................32
4.1
General Guidelines for DF/HCC Institutions ........................................................32
4.2
Registration Process for DF/HCC Institutions.......................................................32
4.3
General Guidelines for Other Investigative Sites ..................................................33
4.4
Registration Process for Other Investigative Sites.................................................33
5.
TREATMENT PLAN........................................................................................................33
5.1
Treatment Regimen................................................................................................33
5.2
Pre-Treatment Criteria ...........................................................................................36
5.3
Agent Administration.............................................................................................37
5.4
General Concomitant Medication and Supportive Care Guidelines......................38
5.5
Criteria for Taking a Participant Off Protocol Therapy.........................................39
5.6
Duration of Follow Up...........................................................................................40
5.7
Criteria for Taking a Participant Off Study ...........................................................40
5.8
Treatment Beyond Disease Progression ................................................................40
6.
DOSING DELAYS/DOSE MODIFICATIONs ................................................................41
6.1
Nivolumab Dose Modifications.............................................................................41
6.2
Bevacizumab Dose Modifications.........................................................................42

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6.3
Rucaparib Dose Modifications ..............................................................................42
6.4
Treatment Modification for Nivolumab-Related Adverse Events.........................46
6.5
Criteria to Resume Treatment Following Nivolumab-Related Adverse 
Events.....................................................................................................................47
6.6
Nivolumab Management Algorithms ....................................................................48
6.7
Treatment Discontinuation Criteria for Nivolumab-Related Adverse 
Events.....................................................................................................................48
6.8
Treatment of Nivolumab Related Infusion Reactions ...........................................49
6.9
Treatment Modification for Bevacizumab-Related Adverse Events.....................50
7.
ADVERSE EVENTS:  LIST AND REPORTING REQUIREMENTS ............................54
7.1
Expected Toxicities................................................................................................54
7.2
Adverse Event Characteristics...............................................................................56
7.3
Serious Adverse Event (SAE)................................................................................56
7.4
Expedited Adverse Event Reporting......................................................................57
7.5
Expedited Reporting to the Food and Drug Administration (FDA) ......................58
7.6
Expedited Reporting to Hospital Risk Management .............................................59
7.7
Routine Adverse Event Reporting .........................................................................59
8.
PHARMACEUTICAL INFORMATION..........................................................................59
8.1
Nivolumab..............................................................................................................59
8.2
Bevacizumab..........................................................................................................65
8.3
Rucaparib...............................................................................................................66
9.
BIOMARKER, CORRELATIVE, AND SPECIAL STUDIES ........................................68
9.1
Biomarker Studies..................................................................................................68
10.
STUDY CALENDAR AND BIOMARKER SAMPLING SCHEDULE .........................73
11.
MEASUREMENT OF EFFECT .......................................................................................75
11.1
Antitumor Effect – Solid Tumors ..........................................................................75
12.
DATA REPORTING / REGULATORY REQUIREMENTS...........................................82
12.1
Data Reporting.......................................................................................................82
12.2
Data Safety Monitoring..........................................................................................83
12.3
Monitoring .............................................................................................................83
12.4
Multicenter Guidelines...........................................................................................83
12.5
Collaborative Agreements Language.....................................................................83
13.
STATISTICAL CONSIDERATIONS...............................................................................83
13.1
Study Design/Endpoints ........................................................................................84
13.2
Sample Size, Accrual Rate and Study Duration ....................................................86
13.3
Stratification Factors..............................................................................................86
13.4
Interim Monitoring Plan ........................................................................................86
13.5
Analysis of Primary Endpoints..............................................................................86
13.6
Analysis of Secondary Endpoints..........................................................................87
13.7
Reporting and Exclusions ......................................................................................87

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14.
PUBLICATION PLAN .....................................................................................................87
REFERENCES ..............................................................................................................................89
APPENDIX A
PERFORMANCE STATUS CRITERIA ..................................................95
APPENDIX B
Safety Algorithms......................................................................................96
APPENDIX c
wHOLE BLOOD GENOTYPING snp COLLECTION iNSTRUCTIONS
104
APPENDIX d
serum soluble biomarkers collection instructions....................................105

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1.
OBJECTIVES
1.1
Study Design
This is a phase II two-arm study with a safety lead-in. Cohort 1 will look at the combination of 
nivolumab, an intravenous monoclonal antibody and inhibitor of the immune checkpoint PD-1, 
and bevacizumab, an intravenous monoclonal antibody against VEGFA and inhibitor of 
angiogenesis, in patients with relapsed epithelial ovarian, fallopian tube or peritoneal cancer. 
Cohort 2 and cohort 3 will look at the combination of nivolumab, bevacizumab, and rucaparib, 
an oral small molecule inhibitor of PARP enzymes, including PARP-1, PARP-2, and PARP-3, 
also in patients with relapsed epithelial ovarian, fallopian tube or peritoneal cancer. Patients on 
all cohorts will receive treatment with nivolumab and bevacizumab every 14 days with one cycle 
consisting of one treatment and undergo restaging every four cycles. Patients on cohort 2 and 
cohort 3 will also receive rucaparib twice daily as continuous dosing. Patients in cohorts 1 and 2 
will be enrolled following a two-stage design with continuation of enrollment to the second stage 
if sufficient anti-tumor activity is seen in the first stage. Patients in cohort 3 will be enrolled in a 
single stage designed for assessment of safety and tolerability.
1.2
Primary Objectives
Cohort 1:  The primary objective is to investigate the objective response rate of nivolumab and 
bevacizumab using RECIST 1.1 criteria or modified GCIG CA-125 criteria. 
Cohort 2:  The primary objective is to investigate the objective response rate of the combination 
of nivolumab, bevacizumab, and rucaparib using RECIST 1.1 criteria or modified GCIG CA-125 
criteria.
Cohort 3:  The primary objective is to investigate the safety and tolerability of the combination 
of nivolumab, bevacizumab, and rucaparib based upon maintenance of dosing without drug 
modifications within the first 100 days of dosing.
1.3
Secondary Objectives
1.  To investigate the safety and observed toxicities of the combination of nivolumab and 
bevacizumab or the combination of nivolumab, bevacizumab, and rucaparib in women with 
relapsed ovarian, fallopian tube, or primary peritoneal cancer.
2.  To investigate the percentage of patients progression-free at 6 months, duration of response, 
and overall response in women with relapsed ovarian, fallopian tube, or primary peritoneal 
cancer receiving nivolumab and bevacizumab or the combination of nivolumab, bevacizumab, 
and rucaparib. In patients in Cohort 3, additional secondary measures of clinical activity will 
include objective response rate by RECIST 1.1 or modified GCIG CA-125 criteria.
3. To investigate immune-related objective response rate and immune-related progression-free 
survival (irPFS) in women with relapsed ovarian, fallopian tube, or primary peritoneal cancer 
receiving nivolumab and bevacizumab or the combination of nivolumab, bevacizumab, and 
rucaparib.
4.  To investigate the association of tumoral PD-L1 in pre-treatment (archival or pre-treatment 
biopsy) with anti-tumor activity of the combination of nivolumab and bevacizumab or the 

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combination of nivolumab, bevacizumab, and rucaparib in women with relapsed ovarian, 
fallopian tube, or primary peritoneal cancer
1.4
Exploratory Objectives
Exploratory translational objectives include:
a.  Evaluation of gene expression immune profiles in association with anti-tumor activity 
of combination nivolumab and bevacizumab or the combination of nivolumab, 
bevacizumab, and rucaparib
b.  Evaluation of somatic mutational burden and alterations in homologous recombination 
pathway genes and association with anti-tumor activity of combination nivolumab and 
bevacizumab or the combination of nivolumab, bevacizumab, and rucaparib
c.  Evaluation of serum cytokines pre-, on-, and post-treatment, and association with anti-
tumor activity of combination nivolumab and bevacizumab or the combination of 
nivolumab, bevacizumab, and rucaparib
2.
BACKGROUND
2.1
Ovarian Cancer
Epithelial ovarian cancer is the third most common and the most lethal gynecologic malignancy, 
with an incidence of 21,980 new cases and approximately 14,270 deaths estimated in 2014 
(Siegel et al., 2014). This disease typically presents at an advanced stage, with a high risk of 
recurrence following first-line platinum-based chemotherapy. In the recurrent setting, treatment 
options for managing relapsed epithelial ovarian cancer (EOC) include platinum-based regimens, 
liposomal doxorubicin, paclitaxel, gemcitabine, bevacizumab, olaparib, and others.  
Bevacizumab, an inhibitor of VEGF-A, is active as a single agent, is generally well-tolerated 
without the usual side effects of cytotoxic chemotherapy, and has reported response rates of 
approximately 16-21% as monotherapy (Cannistra et al., 2007; Burger et al., 2007). In relapsed 
EOC bevacizumab has also been studied in combination with cytotoxic chemotherapy with 
reported response rates of 27% and 79% in the platinum-resistant and platinum-sensitive 
settings, respectively (Pujade-Lauraine et al., 2014; Aghajanian et al., 2012). While there are 
many options for the treatment of relapsed disease, the response rates are generally low, 
remission durations are short, and resistance invariably develops. More effective therapy for 
relapsed EOC represents an important unmet need.
2.2
PD-1 Blockade as Immunotherapy in Oncology
PD-1 (or CD279), a 55-kilodalton Type 1 transmembrane protein, is a member of the CD28 
family of T-cell co-stimulatory receptors that include immunoglobulin super family members 
CD28, CTLA-4, ICOS, and BTLA. PD-1 is highly expressed on activated T cells and B cells.
PD-1 expression can also be detected on memory T-cell subsets with variable levels of 
expression. Two ligands specific for PD-1 have been identified: PD-L1 (also known as B7-H1 or 
CD274) and PD-L2 (also known as B7-DC or CD273). PD-L1 and PD-L2 have been shown to 
down-regulate T-cell activation upon binding to PD-1 in both murine and human systems 
(Freeman et al., 2000; Latchman et al., 2001; Carter et al., 2002). The interaction of PD-1 with 

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its ligands, PD-L1 and PD-L2, expressed on antigen-presenting cells (APCs) and DCs, transmits 
negative regulatory stimuli to down-modulate the activated T-cell immune response. The 
absence or inhibition of PD-1 in murine models has resulted in the development of various 
autoimmune phenotypes and autoimmune diseases (Sharpe et al., 2007). Taken together, these 
results suggest that inhibition of PD-1 binding to its ligands has the potential to activate T-cell 
responses. Since these responses are variable and dependent upon various host genetic factors, 
PD-1 deficiency or inhibition is not accompanied by a universal loss of tolerance to self-
antigens.
Tumors can express tumor-specific antigens as a result of mutational burden, and ongoing 
immune surveillance is believed to control the development of many tumors. Tumor progression 
may depend on the acquisition of mechanisms that permit them to evade an effective immune 
response. One such mechanism of evasion may be the expression of ligands, which engage 
inhibitory receptor(s) on anti-tumor T-cells of many tumors. PD-L1 expression has been found 
on a number of tumors and may be a mechanism by which tumors can directly engage PD-1 to 
evade an effective anti-tumor immune response (Dong et al., 2002; Wintterle et al., 2003; Dong 
et al., 2003). Expression of INF-γ by T cells is known to induce PD-L1 expression in tumors. 
(Pardoll et al., 2012). PD-L1 expression has been associated with poor prognoses in renal 
(Thompson et al., 2004; Thompson et al., 2005; Thompson et al., 2006), esophageal (Ohigashi et 
al., 2005), gastric (Wu et al., 2006) ovarian (Dong et al., 2003), pancreatic (Nomi et al., 2007), 
and lung cancer (Zitvogel et al., 2006). PD-1 engagement on T-cells by PD-L1-positive APC or 
PD-L1-positive tumor cells in the tumor microenvironment may limit effective immune 
responses. Conversely, PD-L1 expression may be a positive prognostic factor as it may indicate 
infiltration of tumor-specific T cells that secrete IFN-γ, which upregulates PD-L1 expression. 
Consistent with this hypothesis is the co-localization of lymphoid cell infiltrates and PD-L1 
staining observed in human melanoma lesions (Taube et al., 2012).
Studies in multiple tumor models using a chimeric murine anti-mouse PD-1 antibody showed 
that PD-1 blockade has anti-tumor activity (Iwai et al., 2005). Blocking PD-1 in PD-L1-positive 
tumors may reverse the inactivation of tumor-specific effector T-cells at the tumor site, as well as 
activate anti-tumor responses that are limited by PD-L1 expression on “host” DC or APC. The 
anti-tumor effects of anti-PD-1 observed in several murine models suggest that both PD-L1-
positive and PD-L1-negative tumors may be targeted using this approach. In addition, in several 
tumor models in which anti-PD-1 has proved ineffective, PD-1 blockade can be combined with 
vaccines or other immunomodulatory antibodies for improved therapeutic efficacy (Hirano et al., 
2005; Li et al., 2009; Curran et al., 2010).
2.3
PARP inhibitors in ovarian cancer
Poly (ADP-ribose) polymerase (PARP) inhibitors (PARPi) are a class of drugs which target the 
DNA repair pathway.  PARPi’s have now been demonstrated to have activity in ovarian cancer 
in a number of different settings, including in relapsed disease (Audeh et al., 2010; Gelmon et 
al., 2011) as well as in a maintenance setting following response to platinum-based 
chemotherapy (Ledermann et al., 2012; Ledermann et al., 2014; Mirza et al., 2016; Pujade-
Lauraine et al., 2017; Coleman et al., 2017).  PARPi’s appear to be particularly active in the 
setting of pre-existing defects in double-strand DNA repair, although activity has been observed 

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in patient populations without evidence of homologous recombination deficiency (Mirza et al., 
2016; Coleman et al., 2017).  Three PARPi’s (rucaparib, olaparib, and niraparib) are currently 
approved by the US FDA for therapy in ovarian cancer in different clinical settings.
Combination therapy with PARPi’s has been an area of growing interest to increase activity and 
overcome drug resistance.  Initial studies investigated the potential of combining PARPi’s with 
chemotherapy; a particular challenge in this setting has been the overlapping toxicity of 
myelosuppression (Matulonis et al., 2017).  As such, combinations of PARPi’s with targeted or 
biologic therapies have been of growing interest, where overlapping myelosuppressive toxicities 
may be avoided.  A Phase 2 study combining the anti-angiogenic cediranib with the PARPi 
olaparib demonstrated significant activity in women with platinum-sensitive ovarian cancer 
compared to olaparib alone (Liu et al., 2014), and Phase 3 trials of this combination are ongoing.  
Additional ongoing trials are investigating the combination of olaparib and bevacizumab 
following initial platinum-based therapy for ovarian cancer and the combination of niraparib and 
bevacizumab in relapsed disease.  Similarly, there has been interest in combining PARPi’s with 
immune checkpoint inhibitors, and recent data have demonstrated activity of combination 
pembrolizumab and niraparib in women with platinum-resistant ovarian cancer, including in 
women without a BRCA mutation (Konstantinopoulos et al., 2018).
2.4
IND Agents
2.4.1
Nivolumab
Mechanism of Action
Nivolumab (also referred to as BMS-936558, MDX1106, ONO-4538) is a fully human 
monoclonal antibody (HuMAb; immunoglobulin G4 [IgG4]-S228P) that targets the programmed 
death-1 (PD-1) cluster of differentiation 279 (CD279) cell surface membrane receptor. PD-1 is a 
negative regulatory molecule expressed by activated T and B lymphocytes. (Sharpe et al., 2007) 
Binding of PD-1 to its ligands, programmed death–ligands 1 (PD-L1) and 2 (PD-L2), results in 
the down-regulation of lymphocyte activation. Inhibition of the interaction between PD-1 and its 
ligands promotes immune responses and antigen-specific T-cell responses to both foreign 
antigens as well as self-antigens.
Summary of Preclinical Studies
Nivolumab has been shown to bind specifically to the human PD-1 receptor and not to related 
members of the CD28 family, such as CD28 inducible co-stimulator (ICOS), cytotoxic T 
lymphocyte antigen-4 (CTLA-4), and B and T lymphocyte attenuator (BTLA) (Nonclinical Study 
Report: Medarex Study No. MDX1106-025-R, 2006; Nonclinical Study Report: Medarex Study 
No. MDX1106-028-R, 2007). Nivolumab inhibits the interaction of PD-1 with its ligands, PD-L1 
and PD-L2, resulting in enhanced T-cell proliferation and interferon-gamma (IFN-γ) release in 
vitro (Velu et al., 2009; Nonclinical Study Report: Medarex Study No. MDX1106-023-R, 2006; 
Nonclinical Study Report: Medarex Study No. MDX1106-032-R, 2006). Fluorescent-activated 
cell sorter (FACS) analysis confirmed that nivolumab binds to transfected CHO and activated 
human T-cells expressing cell surface PD-1 and to cynomolgus monkey PD-1, but not to rat or 
rabbit PD-1 molecules (Nonclinical Study Report: Medarex Study No. MDX1106-025-R, 2006).

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PD-1 inhibition in a mixed lymphocyte reaction (MLR) resulted in a reproducible concentration-
dependent enhancement of IFN-γ release in the MLR up to 50 µg/mL. No effect was observed 
with a human IgG4 isotype control or CD4+ T cells and dendritic cell (DC) controls (Want et al., 
2014).
 
In intravenous (IV) repeat-dose toxicology studies in cynomolgus monkeys, nivolumab was 
well-tolerated at doses up to 50 mg/kg, administered weekly for five weeks, and at doses up to 
50 mg/kg, administered twice weekly for 27 doses. Nivolumab-related findings were limited to a 
reversible decrease of 28% in triiodothyronine (T3) among the females administered 27 doses of 
50 mg/kg. No corresponding changes in the level of thyroxin (T4), thyroid-stimulating hormone 
(TSH), or histologic changes in the thyroid were observed (Nonclinical Study Report: Medarex 
Study No. SUV00025/MDX1106-024-R, 2006; Nonclinical Study Report: Medarex Study No. 
WIL-552003/MDX1106-025-R, 2007).
An enhanced pre- and postnatal development (ePPND) study in pregnant cynomolgus monkeys 
with nivolumab was conducted (BMS-936558: Intravenous Study). Administration of nivolumab 
at up to 50 mg/kg 2QW was well tolerated by pregnant monkeys; however, nivolumab was 
determined to be a selective developmental toxicant when administered from the period of 
organogenesis to parturition at ≥ 10 mg/kg (area under the concentration-time curve [AUC] from 
time zero to 168 hours [AUC(0-168 h)] 117,000 µg•h/mL). Specifically, increased 
developmental mortality (including late gestational fetal losses and extreme prematurity with 
associated neonatal mortality) was noted in the absence of overt maternal toxicity. There were no 
nivolumab-related changes in surviving infants tested throughout the 6-month postnatal period. 
Although the cause of these pregnancy failures was undetermined, nivolumab-related effects on 
pregnancy maintenance are consistent with the established role of PD-L1 in maintaining 
fetomaternal tolerance in mice (Habicht et al., 2007).
Summary of Clinical Studies
Nivolumab has demonstrated clinical activity either as monotherapy or in combination with 
ipilimumab in several tumor types, including non-small cell lung cancer (NSCLC), melanoma, 
and renal cell carcinoma (RCC). The majority of responses were durable and exceeded six 
months (BMS-936558 (nivolumab) Investigator Brochure, 2014). The FDA has approved the use 
of nivolumab to treat patients with metastatic squamous NSCLC with progression on or after 
platinum-based chemotherapy as well as patients with unresectable or metastatic refractory 
melanoma.
Nivolumab was investigated in a phase II study of 18 with platinum-resistant ovarian cancer 
(PROC) (Haminishi et al., 2014). Eligibility for this study required at least two prior lines of 
chemotherapy including a taxane. This was a heavily treated group with 11 of the 18 patients 
having received four or more prior lines of chemotherapy. Despite extensive prior treatment, a 
preliminary response rate of 18% and disease control rate of 44% were reported in this study, 
which compare favorably to results observed with single agent cytotoxic chemotherapy in this 
clinical setting.

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Clinical Pharmacokinetics
Single-dose Pharmacokinetics of Nivolumab
Single-dose PK of nivolumab was studied in 39 subjects with cancer (Clinical Study Report: 
Study No. MDX1106-01, 2011). The single-dose pharmacokinetics (PK) of nivolumab was linear 
and dose-proportional in the range of 0.3 mg/kg to 10 mg/kg. The mean terminal T-HALF of 
nivolumab ranged between 17 and 25 days across the dose range of 0.3 mg/kg to 10 mg/kg. 
Geometric mean total clearance varied from 0.13 mL/h/kg to 0.19 mL/h/kg, while mean volume 
of distribution varied between 83 mL/kg and 113 mL/kg across doses. The clearance and half-
life of nivolumab are consistent with that of IgG4.
Multiple-dose Pharmacokinetics of Nivolumab
The multiple-dose PK of nivolumab given Q2W was determined from MDX1106-03 study as 
well as by population PK (PPK) using data from 669 subjects across nivolumab studies. (Clinical 
Study Report: Study No. MDX1106-03, 2013) Multiple-dose PK of nivolumab following Q2W 
dosing was linear with dose-proportional increase in Cmax and AUC(TAU) in the studied range 
of 0.1 mg/kg to 10 mg/kg. Nivolumab accumulation with Q2W dosing frequency was in the 
range of 2.9 to 3.3 based on AUC(TAU), 2.0 to 2.4 based on Cmax, and 3.1 to 4.8 based on 
Cmin. A PPK model was developed by nonlinear mixed effect modeling using data from 669 
subjects. Nivolumab concentration-time data were well described by a linear, 2-compartment, 0-
order IV infusion model with first-order elimination. Nivolumab PK was found to be linear, dose 
independent, and time invariant. The geometric mean of terminal T-HALF was 25.6 days and the 
typical clearance was 8.8 mL/h, which are consistent with those of full human immunoglobulin 
antibodies. Clearance of nivolumab is independent of dose in the dose range (0.1 mg/kg to 10 
mg/kg) and tumor types studied. Body weight normalized dosing showed approximately constant 
trough concentrations over a wide range of body weights.
Flat (Standardized Dose) of Nivolumab
Nivolumab monotherapy has been extensively studied in a number of tumor types including 
NSCLC, MEL, RCC, and CRC with body weight normalized dosing (mg/kg). Nivolumab 
pharmacokinetics (PK) and exposures of subjects in these studies have been characterized by 
population pharmacokinetic (PPK) analysis of data collected these studies, together with PK data 
from several phase 1, 2, and 3 clinical studies of nivolumab monotherapy in solid tumors. 
Population PK (PPK) analyses have shown that the PK of nivolumab are linear, with dose 
proportional exposures over a dose range of 0.1 mg/kg to 10 mg/kg, and are similar across tumor 
types. Nivolumab clearance and volume of distribution were found to increase with increasing 
body weight, but the increase was less than proportional, indicating that a mg/kg dose represents 
an over-adjustment for the effect of body weight on nivolumab PK. Given the relationship 
between nivolumab PK and body weight, a flat dose is expected to lead to lower exposures in 
heavier patients, relative to the exposures in lighter patients. 
Using the PPK model, nivolumab steady-state trough, peak and time-averaged concentration 
(Cminss, Cmaxss, and Cavgss, respectively) were predicted for a flat nivolumab dose of 240 mg 

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Q2W and compared to those following administration of 3 mg/kg Q2W in NSCLC subjects. A 
dose of 240 mg nivolumab is identical to a dose of 3 mg/kg for subjects weighing 80 kg, which is 
the approximate median body weight of NSCLC subjects in the 3 Phase 2 and 3 BMS clinical 
studies of nivolumab monotherapy.  The geometric mean values of Cminss, Cmaxss, and Cavgss 
with flat dosing are slightly (< 15%) higher than that produced by a 3 mg/kg dose, and the 
coefficient of variation (cv%) in these measures of exposure are only slightly (< 10%) greater 
than that of 3 mg/kg dosing. 
Across the various tumor types in the BMS clinical program, nivolumab has been shown to be 
safe and well tolerated up to a dose level of 10 mg/kg, and the relationship between nivolumab 
exposure produced by 3 mg/kg and efficacy has been found to be relatively flat. Taken together, 
the PK, safety, and efficacy data indicate that the safety and efficacy profile of 240 mg 
nivolumab will be similar to that of 3 mg/kg nivolumab.  Thus a flat dose of 240 mg every 2 
weeks is planned for investigation in this study.
Safety Profile
Most related AEs are thought to be due to the effects of inflammatory cells on specific tissues. A 
variety of preferred terms (PTs) have been used to describe similar kinds of organ-related AEs, 
with the result being that AE frequency tables organized by PTs can lead to underestimation of 
the frequency of similar kinds of organ-related AEs. To address this issue, select AE categories 
were created. Select AE categories group together the most common and impactful PTs by organ 
category. These categories include the following: pulmonary, GI, hepatic, skin, endocrine, 
hypersensitivity/infusion reaction, and renal AEs. It is useful to consider the management of 
nivolumab-related AEs by organ category as the diagnostic work-up often requires excluding 
other potential diagnoses and, when appropriate, instituting specific management principles as 
outlined in the subsequent subsections and Appendix B.
The overall safety experience with nivolumab, as a monotherapy or in combination with other 
therapeutics, is based on experience in approximately 4,000 subjects treated to date. All available 
data suggest that nivolumab monotherapy has a consistent AE profile across tumor types. Across 
all studies conducted to date, treatment-related AEs have included pulmonary toxicity, renal 
toxicity (including acute renal failure), endocrine abnormalities, GI toxicity, dermatologic 
toxicity (including rash), and hepatotoxicity. Most AEs were low-grade (Grade 1-2) with 
relatively few related high-grade (Grade 3-4) AEs. The safety profile is generally consistent 
across completed and ongoing clinical trials, with no maximum tolerated dose (MTD) reached at 
any monotherapy dose tested up to 10 mg/kg. There was no pattern in the incidence, severity, or 
causality of AEs to nivolumab dose level.
In general, the approach to suspected nivolumab-related AEs is similar across any involved 
organ system. Safety management algorithms for organ-specific AEs are found in Appendix B. 
Subjects should have a thorough diagnostic work-up to evaluate potential drug- and non-drug-
related diagnoses. For suspected nivolumab-related AEs, based on the severity of the event, 
management with immunosuppressants may be necessary. In general, dose delays and 
observation are adequate for low-grade AEs. For moderate- and high-grade AEs, 
immunosuppression with corticosteroids should be utilized. Once the AE has begun to improve, 

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corticosteroids can be tapered over approximately three weeks to six weeks (depending on the 
severity of the AE). The management of AEs considered related to any combination treatment is 
similar to the management of AEs caused by either agent alone and utilizes the same safety 
management algorithms.
The safety profile of nivolumab combination therapy varies with the agent combined with 
nivolumab, but is generally consistent with the safety profiles observed with either agent alone 
and, in some cases, the frequency of AEs may be greater than that observed with either agent 
alone.
For nivolumab monotherapy and combination therapy, the majority of AEs have been managed 
successfully with supportive care and, in more severe cases, a combination of dose delay, 
permanent discontinuation, and/or initiation of systemic corticosteroids. Most high-grade events 
were manageable with use of corticosteroids or hormone replacement therapy (endocrinopathies) 
as instructed in the management guidelines provided in Appendix B.
It is rare for a patient receiving immunosuppression for nivolumab-related AEs to develop an 
opportunistic infection. Patients with inflammatory events of any organ category expected to 
require more than four 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. 
Early consultation with an infectious disease specialist should be considered. Depending on the 
presentation, consultation with a pulmonologist for bronchoscopy or a gastroenterologist for 
endoscopy may also be appropriate. In addition, a concomitant opportunistic infection should be 
considered in the differential diagnosis if a patient develops recurrent AEs in the setting of 
ongoing or prior immunosuppressive use. Nivolumab should not be used in subjects with active 
autoimmune disease given the mechanism of action of the antibody.
Clinical Safety of Nivolumab Monotherapy in Combined Advanced Malignancies
A total of 39 and 306 subjects with selected recurrent or treatment-refractory malignancies have 
been treated in a completed phase I single-dose study (MDX1106-01) and a completed phase I 
multidose study (MDX1106-03), respectively (Clinical Study Report: Study No. MDX1106-01, 
2011; Clinical Study Report: Study No. MDX1106-03, 2013). The safety data observed from the 
smaller MDX1106-01 study is similar to the larger and more recent MDX1106-03 study. 
As an overview, review of the safety data by tumor type (RCC, NSCLC, mCRPC, CRC, and 
melanoma) did not show any clinically meaningful differences in the proportion of subjects with 
AEs noted across tumor types. Overall, the safety profile of nivolumab monotherapy was 
generally manageable and was consistent with the mechanism of action of nivolumab. No MTD 
was reached at doses tested up to 10 mg/kg Q2W. The nature, frequency, and severity of any 
causality and treatment-related safety events were similar across tumor types. 
Key safety findings for the subjects in MDX1106-03 are summarized here (Clinical Study 
Report: Study No. MDX1106-03, 2013; Addendum 1 to Final Clinical Study Report for 
MDX1106-03). Drug-related AEs (any grade) were reported in 75.2%, and drug-related Grade 3-
4 AEs were reported in 17.0% of subjects. The most frequently reported drug-related AE was 

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fatigue (28.1%). Other drug-related Grade 3-4 AEs reported in more than two subjects were 
pneumonitis (1.3%), lymphopenia (1.3%), diarrhea (1.0%), abdominal pain (1.0%), CD4 
lymphocytes decreased (1.0%), and hypophosphatemia (1.0%). The most frequently reported 
drug-related SAE was pneumonitis (seven subjects, 2.3%). Drug-related Grade 3-4 pneumonitis 
was reported in four patients (1.3%). The most frequently reported drug-related select AE 
categories (any grade) were skin (24.5%), GI (14.1%), and endocrine (9.5%). AEs belonging to 
the pulmonary and renal select AE categories were unexpected, drug-related toxicities associated 
with the use of nivolumab. AEs belonging to select AE categories were generally manageable 
and reversible with the use of immunosuppressants.
The majority of the deaths reported during MDX1106-03 were due to disease progression. Three 
subjects (1.0%) died due to study drug toxicity at the time of database lock; two out of three 
subjects died within 100 days of last dose of nivolumab, and one died more than 100 days after 
the last dose of nivolumab. The reported causes of death for these three subjects were: non-drug-
related cardiopulmonary arrest due to complications from Grade 5 sepsis (drug-related), drug-
related sepsis, and drug-related respiratory failure secondary to pneumonitis and progressive 
disease. After database lock for the final clinical study report, two subjects were reported to have 
died; both were subjects with NSCLC treated with 3 mg/kg nivolumab. The reported causes of 
death for these two subjects were: drug-related pneumonitis, and non-drug-related infection after 
experiencing drug-related Grade 3 pneumonitis Although not considered to be the primary cause 
of death in all five subjects described above, pneumonitis was considered a contributory factor in 
each case (Weber et al., 2013).
Clinical Safety of Nivolumab Monotherapy in Platinum Resistant Ovarian Cancer
In the phase II study of nivolumab monotherapy in PROC, safety analyses were reassuring with 
limited treatment-related serious adverse events (Hamanishi et al., 2014). Among the 18 patients 
the most common treatment-related adverse events were rash, hypothyroidism, fever, arthralgia 
and lymphocytopenia. For each of these toxicities, the grade 3-4 incidence was low with one 
occurrence reported for each toxicity except for two occurrences reported for hypothyroidism. In 
addition, there were two patients with reported treatment-related serious adverse events (all 
grade 3). For the first patient disorientation, gait disorder and fever were reported; for the second 
patient fever and deep venous thrombosis were reported. There were no treatment-related deaths 
reported in this study.
Clinical Safety of Nivolumab in Combination with Bevacizumab
The safety of nivolumab in combination with bevacizumab has been evaluated in the context of 
NSCLC in two phase I studies, CA209-130 and CA209-012 (Kanda et al., 2014; Rizvi et al., 
2014).
The first study, CA209-130, enrolled a total of 24 patients and evaluated combinations of 
chemotherapy, nivolumab, and bevacizumab for patients with newly diagnosed stage IIIB/IV 
NSCLC who were unsuited to radical radiotherapy or patients with recurrent NSCLC (Kanda et 
al., 2014).  In this study there were six patients who were initially treated the combination of 
carboplatin, paclitaxel, nivolumab, and bevacizumab for six treatment cycles followed by 
maintenance continuation of nivolumab and bevacizumab. In this group of six patients, no DLTs 

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were observed. There was one SAE reported, a patient with grade 2 epistaxis. The combination 
was tolerable with grade 3-4 AEs limited to hematologic toxicities. 
The second study, CA209-012, included evaluation of nivolumab, alone or in combination with 
bevacizumab, as switch maintenance therapy after first-line treatment of advanced NSCLC 
(Rizvi et al., 2014). In this study there were 12 patients who received the combination of 
nivolumab and bevacizumab until disease progression or development of unacceptable toxicity. 
The most commonly reported treatment-related AEs were fatigue, pneumonitis, rhinorrhea, 
cough and diarrhea. Grade 3 treatment-related AEs occurred in four patients (33%) treated with 
this combination; there were no grade 4 treatment-related AEs reported. Four patients (33%) 
discontinued protocol therapy due to treatment-related AEs. 
Across all tumor types including ovarian cancer, all available data indicates that nivolumab 
monotherapy has a tolerable and consistent AE profile. The data for the combination of 
nivolumab in combination with bevacizumab is limited to NSCLC and is also reassuring. A 
safety lead-in is embedded within this study to further characterize the toxicities associated with 
the combination of nivolumab and bevacizumab in ovarian cancer prior to proceeding with full 
enrollment.
2.4.2
Bevacizumab
Bevacizumab is a monoclonal antibody against VEGF-A that has clinical activity in various 
contexts in the treatment of ovarian cancer included as monotherapy in relapsed disease, front-
line maintenance therapy, and in combination with chemotherapy for both platinum-sensitive and 
platinum-resistant disease (Cannistra et al., 2007; Burger et al., 2007; Perren et al., 2011, Burger 
et al., 2011; Aghajanian et al., 2012, Pujade-Lauraine et al., 2014).
Bevacizumab was studied as monotherapy for relapsed disease in two phase II single-arm studies 
(Cannistra et al., 2007; Burger et al., 2007). The first study enrolled 44 patients of whom the 
majority (84%) was platinum resistant and approximately half had received three prior lines of 
chemotherapy. In this study the response rate was 16% and all responses were partial. Regarding 
toxicities, treatment-related grade 3-4 AEs included proteinuria, hypertension, bleeding, and 
wound-healing complications. SAEs included a GI perforation rate of 11% and arterial 
thromboembolism rate of 7% (Cannistra et al., 2007). The second study enrolled 62 patients of 
whom 42% were platinum resistant. This study enrolled less heavily pretreated patients with a 
maximum of two prior cytotoxic regimens. The response rate was 21% of which two were 
complete responses. Grade 3-4 AEs included hypertension, thromboembolism, proteinuria, and 
GI events. There were no perforations, fistulae, or arterial thromboembolic events (Burger et al., 
2007).
With evidence of efficacy as monotherapy in relapsed disease, bevacizumab was also studied 
with chemotherapy in two large phase III phase randomized trials in the front-line setting (Perren 
et al., 2011; Burger et al., 2011). ICON7 studied bevacizumab 7.5mg/kg and randomized 
participants to receive either standard chemotherapy with bevacizumab followed by 
bevacizumab maintenance or standard chemotherapy alone (Perren et al., 2011). The primary 
outcome of this study was progression-free survival. Analysis at 42 months of follow-up showed 
that participants treated with bevacizumab did experience longer PFS, 24.1 months compared to 

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22.4 (P = 0.04). The observed toxicities were in keeping with the earlier studies and included 
hypertension, proteinuria, GI toxicities, bleeding, abscess and fistula formation. GOG-218 also 
studied the incorporation of bevacizumab at 15mg/kg into the primary treatment of ovarian 
cancer but with a somewhat different study design (Burger et al., 2011). In this three-arm 
placebo-controlled study, women were randomized to standard chemotherapy with bevacizumab 
followed by bevacizumab maintenance, standard chemotherapy with bevacizumab followed by 
placebo, or standard chemotherapy with placebo followed by placebo. The primary endpoint 
again was PFS with a significant improvement in PFS observed in the group that received 
bevacizumab both incorporated with front-line chemotherapy and continued as maintenance 
compared to the group that did not receive bevacizumab, 14.1 months and 10.3 months 
respectively (P < 0.001). The toxicity profile in GOG-218 was comparable to that in ICON7.
Finally, bevacizumab has been studied in relapsed ovarian cancer both platinum-sensitive and 
platinum-resistant disease in two large randomized trials. (Aghajanian et al., 2012, Pujade-
Lauraine et al., 2014) In the OCEANS study, participants with platinum-sensitive disease were 
randomized to either carboplatin and gemcitabine with bevacizumab followed by bevacizumab 
maintenance or  carboplatin and gemcitabine with placebo followed by placebo. (Aghajanian et 
al., 2012)The primary outcome was again PFS and the group that received bevacizumab 
demonstrated superior outcome with PFS of 12.4 months compared to 8.4 months (P < 0.0001). 
The AURELIA study randomized participants with platinum-resistant ovarian cancer to either 
chemotherapy with bevacizumab or chemotherapy alone. (Pujade-Lauraine et al., 2014) In this 
study protocol-specified therapy continued until either disease progression or the development of 
unacceptable toxicities. Patients who were randomized to the chemotherapy alone arm were 
allowed to cross over to bevacizumab monotherapy at time of progression. The use of 
bevacizumab again resulted in superior PFS, 6.7 months compared to 3.4 months (P < 0.001). In 
both OCEANS and AURELIA, hypertension and proteinuria were more commonly observed 
among patients treated with bevacizumab.
2.4.3
Rucaparib
Rucaparib is a potent small molecule inhibitor of PARP) enzymes, including PARP-1, PARP-2, 
and PARP-3. Rucaparib has been developed for the treatment of cancer associated with 
homologous recombination deficiency (HRD), defined by the presence of a deleterious mutation 
in the breast cancer gene (BRCA) 1 (BRCA1), breast cancer gene 2 (BRCA2), or another 
homologous recombination repair (HRR) gene, and/or high percentage of tumor genome with 
loss of heterozygosity (tumor genomic loss of heterozygosity [LOH]), which is a phenotypic 
consequence of HRD. Rucaparib is approved in the United States (US) for maintenance 
treatment of adult patients with deleterious BRCA mutation (germline and/or somatic)-associated 
recurrent epithelial ovarian (EOC), fallopian tube (FTC), or primary peritoneal (PPC) cancer 
who are in a complete or partial response to platinum-based chemotherapy. Rucaparib has also 
been approved in the European Union (EU) as monotherapy treatment of adult patients with 
platinum-sensitive, relapsed or progressive, BRCA-mutated (germline and/or somatic), high-
grade EOC, FTC, or PPC who have been treated with 2 or more prior lines of platinum-based 
chemotherapy, and who are unable to tolerate further platinum-based chemotherapy.
The efficacy of rucaparib was investigated in ARIEL3 (NCT01968213), a double-blind, 

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multicenter clinical trial in which 564 patients with recurrent epithelial ovarian, fallopian tube, or 
primary peritoneal cancer who were in response to platinum-based chemotherapy were 
randomized (2:1) to receive rucaparib tablets 600 mg orally twice daily (n=375) or placebo 
(n=189). Treatment was continued until disease progression or unacceptable toxicity. All patients 
had achieved a response (complete or partial) to their most recent platinum-based chemotherapy. 
Randomization was stratified by best response to last platinum (complete or partial), time to 
progression following the penultimate platinum therapy (6 to ≤ 12 months and > 12 months), and 
tumor biomarker status.
Tumor tissue samples were tested using a clinical trial assay (CTA) (N=564) and an 
investigational Foundation Medicine tissue test (n=518). Of the samples evaluated with both 
tests, tumor BRCA (tBRCA) mutant status was confirmed for 99% (177/178) of tBRCA-positive 
patients determined by the CTA. Blood samples for 94% (186/196) of the tBRCA patients were 
evaluated using a central blood germline BRCA test. Based on these results, 70% (130/186) of 
the tBRCA patients had a germline BRCA mutation and 30% (56/186) had a somatic BRCA 
mutation. The efficacy results are based on the tBRCA (germline or somatic) subgroup.
The major efficacy outcome was investigator-assessed progression-free survival (PFS) evaluated 
according to Response Evaluation Criteria in Solid Tumors (RECIST), version 1.1 (v1.1). 
Overall survival (OS) was an additional outcome measure.
Of the 564 enrolled patients, 196 patients (35%) had a tBRCA mutation. Among the patients who 
had a tBRCA mutation, the median age was 58 years (range: 42 to 81) for patients receiving 
rucaparib and 59 years (range: 36 to 84) for those on placebo; the majority were White (84%); 
and 100% had an ECOG performance status of 0 or 1. All patients had received at least two prior 
platinum-based chemotherapies (range: 2 to 5). A total of 33% of patients were in complete 
response (CR) to their most recent therapy. The progression-free interval to penultimate platinum 
was 6-12 months in 41% of patients and > 12 months in 59%. Prior bevacizumab therapy was 
reported for 22% of patients who received rucaparib and 17% of patients who received placebo. 
Measurable disease was present at baseline in 32% of patients. 
ARIEL3 demonstrated a statistically significant improvement in PFS for patients randomized to 
rucaparib as compared with placebo in patients who had a tBRCA mutation. Results from a 
blinded independent radiology review were consistent.
Efficacy results for patients with a tBRCA mutation are summarized below.
Efficacy Results in Patients with tBRCA-mutated Ovarian Cancer – ARIEL3 (Investigator 
Assessment)a

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Kaplan-Meier Curves of Progression-Free Survival in ARIEL3 as Assessed by Investigator: 
tBRCA Group
A final OS analysis was conducted after 130 events were observed. Exploratory OS results 
showed a HR of 0.83 (95% CI: 0.58, 1.19) in the tBRCA subgroup with a median OS of 45.9 
months (95% CI: 37.7, 59.6) for patients treated with rucaparib and 47.8 months (95% CI: 43.2, 
55.8) for patients on placebo.
The most common adverse events reported with rucaparib have primarily been mild to moderate 
in severity, and include gastrointestinal disorders (nausea, vomiting, diarrhea, constipation, and 
abdominal pain), asthenia/fatigue, decreased appetite, and dysgeusia.  The most common grade 3 
or higher adverse events include anemia, increase in transaminases, neutropenia, and fatigue.
Summary of Preclinical Studies
Pharmacological assessment demonstrated that rucaparib is a potent and selective inhibitor of 

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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. 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 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 low 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 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. 
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 embryo-toxic. 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.
Clinical Pharmacokinetics
An overview of data are provided below and described in detail in the rucaparib IB. 
Assessment of rucaparib PK in cancer patients showed an approximate dose-proportional 
exposure after once daily (QD) or BID dosing, rapid absorption with maximum plasma 
concentration (Cmax) achieved within 1.5 to 6 hours, and distribution into tissue. The oral 
bioavailability was 36% and terminal half-life (T1/2) ranged from 9.23 to 33.6 hours.
Rucaparib was moderately bound to human plasma proteins in vitro. 
At a dose of 600 mg BID rucaparib, steady-state was achieved after approximately 1 week. At 
the target clinical dose of 600 mg, a high-fat meal increased the Cmax and area under the plasma 
concentration-time curve from 0 to 24 hours (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.
Population PK Analyses

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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, and no rucaparib dose adjustment is needed when concomitantly 
administered with CYP inhibitors.
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 effect on Pgp. Caution should be exercised in the concomitant use of drugs that are 
substrates of the above CYP enzymes with narrow therapeutic windows.
Safety Profile
An overview of data are provided below and described in detail in the rucaparib IB.
Integrated Safety Analysis
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 decreased, alanine 
aminotransferase (ALT)/aspartate aminotransferase (AST) increased, constipation, decreased 
appetite, and dysgeusia. Commonly experienced Grade 3 or higher TEAEs included 
anemia/hemoglobin decreased, asthenia/fatigue, and ALT/AST increased. Results of a more 
recent integrated safety analysis for rucaparib treatment in over 900 patients with ovarian cancer 
who received 600 mg BID rucaparib in either 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, ALT/AST increased, decreased appetite, 
and dysgeusia. The most common TEAEs≥ Grade 3 included anemia/decreased hemoglobin, 
ALT/AST increased, neutropenia/decreased absolute neutrophil count (ANC), and 
asthenia/fatigue.
The laboratory abnormalities were consistent with the TEAEs, with decreased hemoglobin (and 
associated increase in mean corpuscular volume [MCV] and mean corpuscular hemoglobin 
[MCH]), increased ALT, increased AST, and increased serum creatinine, most commonly 
occurring. Decreased platelets, neutrophils, leukocytes, lymphocytes, and increased cholesterol 
were observed to a lesser extent. The transient elevations in ALT/AST with rucaparib treatment 
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 

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patients discontinued rucaparib due to ALT/AST elevations. 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. 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.
Adverse Events of Special Interest (AESIs)
An overview of data are provided below and described in detail in the rucaparib IB. 
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 (eg, 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 a deleterious BRCA mutation (8, 9). Based on these confounding 
factors, there is insufficient scientific evidence to conclude that MDS and AML are causally 
related to rucaparib.  
Adverse events of pneumonitis have been reported with PARP inhibitor treatment, including in 
clinical trials evaluating rucaparib.  Currently, however, there is a lack of understanding of a 
mechanistic link between pneumonitis and PARP inhibitor treatment, and causality assessment is 
often confounded by lack of a consistent clinical pattern as well as other pre-disposing factors, 
such as cancer and/or metastases in lungs, underlying pulmonary disease, smoking history, 
and/or previous chemotherapy and radiotherapy.  In order to gather the necessary information to 
enable a thorough evaluation and assessment to better understand whether or not there is a 
relationship between pneumonitis and rucaparib treatment, pneumonitis has been classified as an 
AESI.
On 01 May 2023, pharmaand Schweiz GmbH (Pharma&) acquired the rights to and assumed 
regulatory responsibility for rucaparib from Clovis Oncology, Inc (Clovis).
2.5
Study Rationale
Preclinical and early-phase clinical data suggest that immune modulation represents a treatment 
strategy that is worthy of further investigation in relapsed EOC. One method by which tumor 
cells may evade immune surveillance is by activation of the programmed cell death (PD-1) 
pathway, mediated by expression of PD-1 on the surface of T lymphocytes, which conveys an 
inhibitory signal after binding to its ligand PD-L1 on the surface of tumor cells. This mechanism 
seems applicable to ovarian cancer and it is noteworthy that higher tumoral expression of PD-L1 
is associated with inferior prognosis (Hamanishi et al., 2007) .

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Both nivolumab and bevacizumab show activity as monotherapies in previously treated relapsed 
EOC with single-agent response rates of approximately 16-18% (Hamanishi et al., 2014; 
Cannistra et al., 2007; Burger et al., 2007). Regarding the safety of the combination, the toxicity 
profiles of these targeted agents do not seem to overlap and safety analyses of the combination in 
phase I studies in NSCLC did not reveal any unexpected toxicity signals (Kanda et al., 2014; 
Rizvi et al., 2014).
In addition to these encouraging early-phase clinical efficacy and safety data, there is reason to 
believe that there is cross-talk between immune checkpoint regulation mediated by the PD-1 
pathway, and VEGF-induced angiogenesis. It is increasingly appreciated that VEGF is not only 
involved in stimulating angiogenesis, but plays an immune suppressive function as well. In 
particular, VEGF has been shown to impair dendritic cell (DC) function and maturation, which 
has been postulated to inhibit effective antigen presentation by DCs in humans, as well as in 
murine models (Motz et al., 2011; Takahashi et al., 2004; Gabrilovich et al., 1996). Furthermore, 
inhibition of tumor derived VEGF in murine models of angiogenesis has been shown to improve 
DC numbers and function.  Importantly, it has been shown that tumor-derived VEGF-A is a 
potent inducer of PD-L1 expression in preclinical murine models (Curiel et al., 2003), thus 
establishing the potential for in vivo cross-talk between the angiogenic and immune checkpoint 
pathways. These preclinical data make it reasonable to hypothesize that there may be synergy in 
simultaneously blocking both VEGF as well as PD-1 in patients with relapsed EOC.
Other clinical studies have demonstrated that PARP inhibitors and bevacizumab can be 
combined with minimal overlapping toxicities (ongoing AVANOVA study; Dean et al., Br J 
Cancer 2012), and both pre-clinical and clinical studies suggest that anti-angiogenics and PARP 
inhibitors could potentially have synergistic effects (Liu et al., Lancet Oncol 2014; Bindra et al., 
Oncogene 2007; Chan et al., Cancer Res 2010).  Similarly, pre-clinical studies also suggest that 
PARP inhibitors alone can have immunoregulatory effects (Huang et al., Biochem Biophys Res 
Comm 2015; Jiao et al., Clin Cancer Res 2017), and that, in combination with immune 
checkpoint inhibitors, can have synergistic effects (Higuchi et al., Cancer Immunol Res 2015).  
These studies provide rationale for exploring the combination of PARP inhibitors with immune 
checkpoint inhibitors in recurrent ovarian cancer.  Based on these multiple mechanisms of 
synergy between these three classes of agents, it is possible a “triplet combination” of 
nivolumab, bevacizumab, and rucaparib could lead to even greater activity in women with 
recurrent ovarian cancer.
 
2.6
Rationale for Cohort 3
22 total patients were enrolled to Cohort 2 of the study; 5 patients were enrolled to the initial 
safety lead-in including rucaparib 600mg orally twice daily, nivolumab 240mg IV q2weeks, and 
bevacizumab 10mg/kg IV q2weeks. This dose level was deemed not tolerable after 2 patients 
developed a DLT (1 grade 3 hematuria, 1 grade 3 LFT elevation). Enrollment proceeded at the 
protocol-specified DL -1 of rucaparib 500mg orally twice daily, nivolumab 240mg IV q2weeks, 
and bevacizumab 10mg/kg IV q2weeks. A total of 17 patients were enrolled at this dose level to 
the first stage of this Cohort per protocol (1 patient was not evaluable for response and was 
replaced). While the clinical activity in this cohort met the pre-specified criteria to proceed to 

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stage 2 of this two-stage design (4 partial responses were observed), 13 of the 17 patients had 
discontinuation of at least one of the study medications, with multiple patients requiring multiple 
dose reductions of rucaparib, suggesting poor tolerability of the regimen when rucaparib is dosed 
at 500mg twice daily.  Notably, no concerns regarding safety or tolerability were observed with 
the combination of nivolumab 240mg IV q2weeks and bevacizumab 10mg/kg IV q2weeks 
dosing regimen, as reported in Cohort 1 of this study (Liu et al., JAMA Oncol 2019).
A “triplet” regimen of combined PARP inhibition, PD-1 inhibition, and an anti-angiogenic agent 
remains of interest in ovarian cancer, due to potential for synergistic activity, as detailed in 
Section 2.5.  Clinical data have supported the potential for significant activity, particularly in 
patients with platinum-sensitive disease.  In the MEDIOLA study, Drew and colleagues reported 
an 87.1% response rate with a median PFS of 14.7 months and a median duration of response of 
11.1 months in women with BRCA wild-type platinum-sensitive recurrent ovarian cancer to the 
combination of the PARP inhibitor olaparib, the PD-L1 inhibitor durvalumab, and the anti-
angiogenic agent bevacizumab (Drew et al., ESMO 2020 Virtual Congress).  58% of patients had 
a platinum-free interval of 6 to 12 months, and activity was observed regardless of genomic 
instability status, as assessed by Foundation Medicine next generation sequencing.
Given the potential activity of this triplet combination but challenges with tolerability with 
rucaparib dosed at 600mg twice daily or 500mg twice daily, we therefore propose a cohort to 
assess the safety and tolerability of this triplet combination when rucaparib is dosed at 300mg 
twice daily, with a secondary assessment of efficacy in a platinum sensitive population.
 
2.7
Correlative Studies Background
Exploratory correlative studies aim to identify potential predictive biomarkers of nivolumab plus 
bevacizumab therapy in subjects with ovarian cancer. Data from these investigations will be 
evaluated for associations with response, survival (OS, PFS) and/or safety (adverse event) data. 
All samples collected may also be used for future exploratory analyses (unless restricted by local 
requirements) to assess biomarkers associated with ovarian cancer or immunotherapy plus 
antiangiogenic treatment.
Correlative studies include evaluation of tumoral PD-L1 expression, evaluation of tumoral 
genomic signatures, homologous recombination deficiency (HRD) status, mutational status, and 
serum biomarker profiling.
Evaluation of tumoral PD-L1 expression 
Given their mechanism of action, tumoral PD-L1 expression has been predicted to be a possible 
biomarker of response to PD-1/PD-L1 blockade. Studies have suggested higher response rates to 
mediators of PD-1/PD-L1 blockade in patients with PD-L1 expressing tumors (Topalian et al., 
2012; Weber et al., 2013; Herbst et al., 2014).  However, some patients without PD-L1 
expression within their tumors have still exhibited significant response to PD-1/PD-L1 blockade. 
Tumor PD-L1 overexpression has shown to be a negative prognostic factor in patients with 
ovarian cancer (Hamanishi et al., 2007). However, because of the fact that the PD-L1/PD-1 
interaction promotes immune escape in human ovarian cancers (Lavoue et al., 2013), high PD-

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L1 expression in ovarian tumors may be present in patients that better respond to anti-PD-1 
therapy when compared to patients with low tumor PD-L1 expression. In this context, the 
analysis of PD-L1 expression in tumor samples can help elucidate whether expression of PD-L1 
in ovarian cancer is predictive of response to anti-PD-1 therapy.  
Evaluation of tumoral genomic signatures 
Genomic analyses of tumor biopsies may provide with a comprehensive tumor immunoprofiling 
of ovarian cancer. In 2011, the cancer genome atlas research network (TCGA) described four 
phenotypes of ovarian cancer based on gene expression analysis: immunoreactive, differentiated, 
proliferative, and mesenchymal (TCGA, 2011). Among these, the mesenchymal group was 
associated with shorter OS, while the immunoreactive group showed the highest TILs and a link 
between anti-tumor B-cell activity and longer survival (Iglesia et al, 2014).
Gourley and colleagues described a three-group gene expression-based classification of ovarian 
cancer: immune, proangiogenic, and immune/proangiogenic. The immune subgroup was 
accompanied by superior survival compared to the other groups. However, the addition of 
bevacizumab significantly reduced clinical outcome in the immune subgroup while showed a 
trend toward PFS benefit in the proangiogenic group in a post-hoc analysis of data from the 
ICON7 trial (Gourley et al., 2014).  Additionally, the ESTIMATE score (described by Yoshihara 
et al., 2013), which utilizes gene expression signatures to infer the fraction of stromal and 
immune cells in tumor samples, may also allow for classification of ovarian cancers based upon 
degree of immune infiltration.  
Analysis of these tumor-associated normal cells in tumor tissues may provide insights into tumor 
biology and aid in the development of prognostic and predictive models. We therefore propose to 
explore the correlation of tumoral genomic signatures with clinical outcomes in patients 
receiving combination of nivolumab with bevacizumab.  
Evaluation of mutational and HRD status
Genomic BRCA mutations, as well as total mutational burden, have been associated with 
response to in patients with high grade serous ovarian cancer (Birkbak et al. PLOSone 8:e80023, 
2013).  In addition, hyper mutated ovarian tumors may be associated with high immune 
infiltration. This study will investigate whether mutational load may identify subjects that better 
respond to nivolumab plus bevacizumab therapy. The mutational and HRD status of patients 
with ovarian cancer will be assessed to evaluate the impact of genomic alterations on 
susceptibility to the combination of nivolumab and bevacizumab of tumor biopsies may provide 
with a comprehensive tumor immunoprofiling of ovarian cancer. 
Evaluation of serum biomarkers
A pre-existing pro-inflammatory cytokine profile as well as an increase of pro-inflammatory 
cytokines during therapy may represent a pharmacodynamic biomarker of response to anti-PD-1 
treatment (Zaretsky et al., 2015). In addition, high VEGF levels in the peripheral blood are 
almost invariably associated with poor outcomes (Zhu, et al, Nat Rev Clin Oncol, 2011), which 

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is indicative of its prognostic biomarker value. An increase of soluble VEGF and soluble VEGF 
receptors may both indicate pharmacodynamic effect and toxicity of bevacizumab therapy. For 
example, circulating levels of neuropilin-1, VEGF-A, and genetic variants in VEGFA or its 
receptors are proposed as biomarker candidates for therapy with bevacizumab (Lambrechts, et al, 
JCO, 2013). Furthermore, PlGF changes may have pharmacodynamic biomarker value and the 
increase of PIGF can mediate resistance to bevacizumab (Duda, et al, Oncologist, 2010). Finally, 
pre-existing high levels of soluble VEGFR-1 can also be considered as a negative predictor 
biomarker of response to bevacizumab in cancer (Duda, et al, ISRN Cell BIol, 2012).  Therefore, 
exploratory investigation of serum biomarkers of response to combined nivolumab and 
bevacizumab will also be incorporated in this study.
3.
PARTICIPANT SELECTION
3.1
Eligibility Criteria 
3.1.1
Participants must have histologic or cytologic confirmation of epithelial ovarian cancer, 
fallopian tube or peritoneal cancer. All histologies (including serous, mucinous, 
endometrioid, clear cell, MMMTs, and mixed histologies) are eligible. All tumor grades 
are eligible.
3.1.2
Participants must have received a first-line platinum-based chemotherapy regimen
3.1.3
Participants must have relapsed disease despite standard therapy.
3.1.4
For Cohorts 1 and 2:  Participants with platinum-resistant or platinum-sensitive disease 
(within 12 months) are eligible. Platinum-resistant disease is defined as relapse within 6 
months after the last dose of platinum-based chemotherapy. Platinum-sensitive disease is 
defined as relapse greater than 6 months after the last dose of platinum-based 
chemotherapy. Participants with platinum-sensitive disease who have experienced relapse 
within 6 to 12 months after the last dose of platinum-based chemotherapy are eligible. 
Participants with primary platinum-refractory disease (defined as progression during or 
relapsed within 2 months of their initial platinum-based chemotherapy) are not eligible.
For Cohort 3:  Particpants must have platinum-sensitive disease and have experienced 
relapse within 6 to 12 months (i.e., 180 to 365 days) after the last dose of platinum-based 
chemotherapy.
3.1.5
Participants must have received no more than 3 prior chemotherapy or cytotoxic 
regimens. There is no limit to the number of prior hormonal therapies.
3.1.6
Participants must have measurable disease by RECIST 1.1 criteria.
3.1.7
Participants who have received prior bevacizumab are eligible unless there is evidence of 
unacceptable toxicity due to prior bevacizumab exposure.

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3.1.8
Participants may not have received any prior treatment with an anti-PD-1, anti PD-L1, 
anti-PD-L2, anti-CTLA-4 antibody, or any other antibody or drug specifically targeting 
T-cell co-stimulation or immune checkpoint pathways.
3.1.9
Participants must have stopped any hormonal therapy at least 1 week prior to treatment 
with nivolumab and bevacizumab. Participants may continue on hormone replacement 
therapy administered for post-menopausal symptoms.
3.1.10 Age ≥ 18 years
3.1.11 Estimated life expectancy of greater than 6 months.
3.1.12 ECOG performance status of 0 or 1 (Appendix A)
3.1.13 Screening laboratory values must meet the following criteria and should be obtained 
within 14 days prior to registration:

WBC ≥ 2,000/µL

Absolute neutrophil count ≥ 1,500/µL

Platelets ≥ 100,000/mcL

Hemoglobin ≥ 9.0 g/dL

Serum creatinine less than or equal to the institutional ULN or creatinine clearance 
(CrCl) ≥ 60 mL/min (calculated using the Cockgroft-Gault formula) for participants 
with serum creatinine levels above institutional ULN

AST (SGOT) / ALT (SGPT) ≤ 3 × institutional ULN

Total bilirubin ≤ 1.5 × institutional ULN (except participants with Gilbert Syndrome, 
who can have total bilirubin ≤ 3.0 × institutional ULN with direct bilirubin that is 
within institutional ULN)

Coagulation parameters (INR, aPTT) ≤ 1.25 × institutional ULN
3.1.14 Patients with treated limited stage basal cell or squamous cell carcinoma of the skin or 
carcinoma in situ of the breast or cervix are eligible. Patients with stage IA endometrial 
cancer are eligible if the following conditions are met: without vascular or lymphatic 
invasion AND no serous, clear cell or grade 3 histology. Patients with early stage I or II 
cancers treated with curative intent who have no evidence of recurrent cancer 3 years 
following diagnosis and judged by the investigator to be at low risk of recurrence are 
eligible.
3.1.15 Participants must have biopsiable disease and be willing to undergo pre-treatment biopsy, 
or have an archival tumor sample obtained < 20 months prior to study entry.

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3.1.16 Women of childbearing potential (WOCBP) is defined as any female who has 
experienced menarche and who has not undergone surgical sterilization (hysterectomy or 
bilateral oophorectomy) or who is not postmenopausal. Menopause is defined clinically 
as 12 months of amenorrhea in a woman over 45 in the absence of other biological or 
physiological causes. Additionally, women under the age of 62 who are not surgically 
sterile must have a documented serum follicle stimulating hormone (FSH) level less than 
40 mIU/mL to document postmenopausal status.
Nivolumab, bevacizumab, and rucaparib may each cause fetal harm or risk to human 
pregnancy. For this reason, WOCBP must agree to use appropriate method(s) of 
contraception for 6 months after the last dose of study treatment, per FDA 
recommendations on use of contraception following bevacizumab. Should a woman 
become pregnant or suspect she is pregnant while participating in this study, she should 
inform her treating physician immediately.  Patients receiving rucaparib should 
immediately discontinue rucaparib if they should become pregnant or suspect they are 
pregnant
3.1.17 WOCBP must have a negative serum or urine pregnancy test (minimum sensitivity 25 
IU/L or equivalent units of HCG) within 24 hours prior to the start of study treatments.
3.1.18 Women must not be breastfeeding
3.1.19 Ability to understand and the willingness to sign a written informed consent document.
3.1.20 Specific criteria for Cohorts 2 and 3
3.1.20.1
Patients must have undergone germline BRCA testing and must not have 
a deleterious or suspected deleterious BRCA mutation.  Where tumor testing has been 
performed, patients with a deleterious or suspected deleterious somatic BRCA 
mutation are also not eligible.
3.2
Exclusion Criteria
3.2.1
Patients with primary platinum-refractory disease are ineligible.  Primary platinum-
refractory disease is defined as relapse less than 2 months after initial platinum-based 
chemotherapy.
3.2.2
Patients with platinum-sensitive disease with relapse greater than 12 months after the last 
dose of platinum-based chemotherapy are ineligible.
3.2.3
Participants who have had chemotherapy or radiotherapy within 3 weeks prior to entering 
the study or those who have not recovered from adverse events due to agents 
administered more than 3 weeks earlier.

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3.2.4
Participants may not be receiving any other investigational agents nor have participated 
in an investigational trial within the past 4 weeks.
3.2.5
Participants must agree not to use natural herbal products or other “folk remedies” while 
participating in this study.
3.2.6
Patients with a history of allergic reactions attributed to bevacizumab or to compounds of 
similar chemical or biologic composition to nivolumab or bevacizumab are excluded.
3.2.7
Patients are excluded if they have active brain metastases or leptomeningeal metastases. 
Subjects with brain metastases are eligible if metastases have been treated and there is no 
magnetic resonance imaging (MRI) evidence of progression for at least 6 months after 
treatment is complete and within 28 days prior to the first dose of nivolumab and 
bevacizumab administration. There must also be no requirement for immunosuppressive 
doses of systemic corticosteroids (> 10 mg/day prednisone equivalents) for at least 2 
weeks prior to study drug administration.
3.2.8
Patients with any of the following cardiovascular diseases are excluded:
3.2.8.1
History of myocardial infarction within six months
3.2.8.2
Unstable angina
3.2.8.3
Angina pectoris that requires the use of anti-anginal medication
3.2.8.4
History of documented congestive heart failure (NYHA classification of 
III or IV) or documented cardiomyopathy
3.2.8.5
Valvular disease with documented compromise in cardiac function
3.2.8.6
If cardiac function assessment is clinically indicated or performed:
LVEF less than normal per institutional guidelines, or < 55%, if threshold 
for normal not otherwise specified by institutional guidelines
Patients with the following risk factor should have a baseline cardiac 
function assessment:

Prior treatment with anthracyclines
3.2.8.7
Any prior history of hypertensive crisis or hypertensive
encephalopathy
3.2.8.8
Patients may not have any evidence of pre-existing inadequately
controlled hypertension (defined as a systolic BP of >140 mmHg or a 
diastolic BP of >90 mmHg), and must have a normal blood pressure 
(≤140/90 mmHg) taken in the clinic setting by a medical professional 
within 2 weeks prior to starting study.
3.2.8.9
Clinically significant peripheral vascular disease
3.2.8.10
Vascular disease including aortic aneurysm or dissection
3.2.8.11
History of stroke, transient ischemic attack or subarachnoid hemorrhage
3.2.8.12
Ventricular arrhythmias except for benign premature ventricular 
contractions
3.2.8.13
Cardiac conduction abnormality requiring a pacemaker
3.2.8.14
Known history of QT/QTc prolongation or torsades de pointes

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3.2.8.15
QTc prolongation > 470 msec or other significant ECG abnormality noted 
during screening
3.2.9
Grade 2 or higher proteinuria (2+ or higher protein on urinalysis or urine 
protein:creatinine (UPC) ratio ≥ 1.0; if both tests are performed, UPC should be used to 
evaluate eligibility) or hematuria.
3.2.10 Participants may not have evidence of a bowel obstruction, abdominal fistula, or intra-
abdominal abscess within 6 months of study entry. Participants with current signs or 
symptoms suggestive of bowel obstruction including early or partial obstruction are 
ineligible. Participants with a history of gastrointestinal perforation at any time point are 
ineligible.
3.2.11 Non-healing wound, ulcer or bone fracture.
3.2.12 Serious active infection requiring intravenous antibiotics and/or hospitalization at study 
entry.
3.2.13 Current dependency on IV hydration or TPN.
3.2.14 Any patient with a history of major depressive episode, bipolar disorder, 
obsessive/compulsive disorder, schizophrenia, a history of suicide attempt or ideation, or 
homicide/homicidal ideation as judged by the investigator and/or based on recent 
psychiatric assessment may not participate in this study without discussion with and 
agreement of the study PI.
3.2.15 Uncontrolled current illness including, but not limited to, ongoing or active infection or 
psychiatric illness/social situations that would limit compliance with study requirements.
3.2.16 Patients are excluded if they have an active, known or suspected autoimmune disease 
other than the following: vitiligo, type I diabetes mellitus, residual hypothyroidism due to 
autoimmune condition only requiring hormone replacement, psoriasis not requiring 
systemic treatment, or conditions not expected to recur in the absence of an external 
trigger.
3.2.17 Patients are excluded if they have a condition requiring systemic treatment with either 
corticosteroids (> 10 mg daily prednisone equivalents) or other immunosuppressive 
medications within 14 days of study drug administration, with the exception of a brief 
course of corticosteroids for prophylaxis (e.g., contrast dye allergy) or for treatment of 
non-autoimmune conditions (e.g., delayed-type hypersensitivity reaction caused by 
contact allergen).  Participants are permitted to use topical, ocular, intra-articular, 
intranasal, and inhalational corticosteroids (with minimal systemic absorption).

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3.2.18 Patients are excluded if they test positive for hepatitis B virus surface antigen (HBV sAg) 
or hepatitis C virus ribonucleic acid (HCV antibody) indicating acute or chronic 
infection.
3.2.19 Patients are excluded if they have known history of testing positive for human 
immunodeficiency virus (HIV) or known acquired immunodeficiency syndrome (AIDS).
3.2.20 Evidence of prior or current coagulopathy or bleeding diathesis.
3.2.21 Major surgical procedure, open biopsy, or significant traumatic injury within 28 days 
prior to starting nivolumab and bevacizumab
3.2.22 History of severe infusion reactions to monoclonal antibody therapy
3.2.23 Specific criteria for Cohorts 2 and 3
3.2.23.1
Patients who have received a prior PARP inhibitor are not allowed to 
enroll to Cohort 2 of the trial
3.2.23.2
Patients are excluded from Cohort 2 and Cohort 3 should they have pre-
existing duodenal stent and/or any gastrointestinal disorder or defect that would, in 
the opinion of the investigator, interfere with absorption of rucaparib.
3.3
Inclusion of Women and Minorities
Women of all races and ethnic groups are eligible for this trial. This disease does not affect men.
4.
REGISTRATION PROCEDURES
4.1
General Guidelines for DF/HCC Institutions
Institutions will register eligible participants in the Clinical Trials Management System (CTMS) 
OnCore. Registrations must occur prior to the initiation of protocol therapy. Any participant not 
registered to the protocol before protocol therapy begins will be considered ineligible and 
registration will be denied.
An investigator will confirm eligibility criteria and a member of the study team will complete the 
protocol-specific eligibility checklist.
Following registration, participants may begin protocol therapy. Issues that would cause 
treatment delays should be discussed with the Overall Principal Investigator (PI). If a participant 
does not receive protocol therapy following registration, the participant’s registration on the 
study must be canceled. Registration cancellations must be made in OnCore as soon as possible. 
4.2
Registration Process for DF/HCC Institutions

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33
DF/HCC Standard Operating Procedure for Human Subject Research Titled Subject Protocol 
Registration (SOP #: REGIST-101) must be followed.  
4.3
General Guidelines for Other Investigative Sites
N/A
4.4
Registration Process for Other Investigative Sites
N/A
5.
TREATMENT PLAN
5.1
Treatment Regimen
Cohort 1
Each cycle will be 14 days with nivolumab and bevacizumab administered on day 1 of each 
cycle. Treatment will be administered on an outpatient basis. Expected toxicities and potential 
risks for nivolumab and bevacizumab are described in Section 7 (Adverse Events: List and 
Reporting Requirements). No investigational or commercial agents or therapies other than those 
described below may be administered with the intent to treat the participant's malignancy.
The treatment dose of nivolumab is 240 mg. The starting dose for bevacizumab is 10 mg/kg. No 
dose reductions or escalations will be allowed for nivolumab. One dose reduction will be 
allowed for bevacizumab. Dosing delays and modifications are described in Section 6 (Dosing 
Delays/Dose Modifications). In cases where cycles may be shortened or extended, a minimum of 
12 days must pass between consecutive infusions of nivolumab and bevacizumab. 
Regimen Description
Agent
Premedications; 
Precautions
Dose
Route
Schedule
Cycle 
Length
Nivolumab
No premedication or 
hydration necessary. 
Subjects should be 
carefully monitored 
for infusion reactions 
during nivolumab 
administration. If an 
acute infusion 
reaction is noted, 
subjects should be 
managed according 
240 mg
IV over 30 
minutes before 
bevacizumab
Day 1
14 days 

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to Protocol Section 
5.3 & 6.7
Bevacizumab
No premedication or 
hydration necessary
10 mg/kg 
(dosing 
weight may 
be actual 
body weight 
or per 
institutional 
guidelines) 
IV over 30 
minutes (though 
infusion duration 
may vary per 
institutional 
guidelines) after 
nivolumab. Begin 
bevacizumab 
infusion 30 
minutes after 
conclusion of 
nivolumab 
infusion.
Day 1
(2 weeks)
Cohort 2
Each cycle will be 14 days with nivolumab and bevacizumab administered on day 1 of each 
cycle. Rucaparib will be taken twice daily by the patient on a continuous schedule. Treatment 
will be administered on an outpatient basis. Expected toxicities and potential risks for 
nivolumab, bevacizumab, and rucaparib are described in Section 7 (Adverse Events: List and 
Reporting Requirements). No investigational or commercial agents or therapies other than those 
described below may be administered with the intent to treat the participant's malignancy.
The treatment dose of nivolumab is 240 mg. The starting dose for bevacizumab is 10 mg/kg. The 
starting dose for rucaparib is 600mg twice daily. No dose reductions or escalations will be 
allowed for nivolumab. One dose reduction will be allowed for bevacizumab. Up to three dose 
reductions will be allowed for rucaparib. Dosing delays and modifications are described in 
Section 6 (Dosing Delays/Dose Modifications). In cases where cycles may be shortened or 
extended, a minimum of 12 days must pass between consecutive infusions of nivolumab and 
bevacizumab.
Regimen Description
Agent
Premedications; 
Precautions
Dose
Route
Schedule
Cycle 
Length
Nivolumab
No premedication or 
hydration necessary. 
Subjects should be 
carefully monitored 
for infusion reactions 
during nivolumab 
administration. If an 
240 mg
IV over 30 
minutes before 
bevacizumab
Day 1

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acute infusion 
reaction is noted, 
subjects should be 
managed according 
to Protocol Section 
5.3 & 6.7
Bevacizumab
No premedication or 
hydration necessary
10 mg/kg 
(dosing 
weight may 
be actual 
body weight 
or per 
institutional 
guidelines) 
IV over 30 
minutes (though 
infusion duration 
may vary per 
institutional 
guidelines) after 
nivolumab. Begin 
bevacizumab 
infusion 30 
minutes after 
conclusion of 
nivolumab 
infusion.
Day 1
Rucaparib
No premedications or 
hydration necessary
600 mg
PO
BID days 
1 through 
14 
14 days 
(2 weeks)
An initial safety lead-in of 6 patients shall be enrolled to this cohort at a dose of rucaparib 600mg 
twice daily prior to expansion to full enrollment.  Should two or more patients experience a DLT 
at this dose level, a second safety cohort of 6 patients will be enrolled to this cohort at a dose of 
rucaparib 500mg twice daily.  
Cohort 3
Each cycle will be 14 days with nivolumab and bevacizumab administered on day 1 of each 
cycle. Rucaparib will be taken twice daily by the patient on a continuous schedule. Treatment 
will be administered on an outpatient basis. Expected toxicities and potential risks for 
nivolumab, bevacizumab, and rucaparib are described in Section 7 (Adverse Events: List and 
Reporting Requirements). No investigational or commercial agents or therapies other than those 
described below may be administered with the intent to treat the participant's malignancy.
The treatment dose of nivolumab is 240 mg. The starting dose for bevacizumab is 10 mg/kg. The 
starting dose for rucaparib is 300mg twice daily. No dose reductions or escalations will be 
allowed for nivolumab. One dose reduction will be allowed for bevacizumab. One dose 
reduction will be allowed for rucaparib. Dosing delays and modifications are described in 
Section 6 (Dosing Delays/Dose Modifications). In cases where cycles may be shortened or 
extended, a minimum of 12 days must pass between consecutive infusions of nivolumab and 
bevacizumab.

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Regimen Description
Agent
Premedications; 
Precautions
Dose
Route
Schedule
Cycle 
Length
Nivolumab
No premedication or 
hydration necessary. 
Subjects should be 
carefully monitored 
for infusion reactions 
during nivolumab 
administration. If an 
acute infusion 
reaction is noted, 
subjects should be 
managed according 
to Protocol Section 
5.3 & 6.7
240 mg
IV over 30 
minutes before 
bevacizumab
Day 1
Bevacizumab
No premedication or 
hydration necessary
10 mg/kg 
(dosing 
weight may 
be actual 
body weight 
or per 
institutional 
guidelines) 
IV over 30 
minutes (though 
infusion duration 
may vary per 
institutional 
guidelines) after 
nivolumab. Begin 
bevacizumab 
infusion 30 
minutes after 
conclusion of 
nivolumab 
infusion.
Day 1
Rucaparib
No premedications or 
hydration necessary
300 mg
PO
BID days 
1 through 
14 
14 days 
(2 weeks)
5.2
Pre-Treatment Criteria
5.2.1
Cycle 1, Day 1
If screening labs are performed greater than 3 days prior to Cycle 1 Day 1, labs must be repeated 
on Cycle 1 Day 1 and must meet eligibility criteria. The patient may not start on study treatment 
until Cycle 1 Day 1 labs meet eligibility criteria. If screening labs are performed within 3 days 
prior to Cycle 1 Day 1, and meet eligibility criteria, labs do not need to be repeated on Cycle 1 

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Day 1 unless the investigator believes they are likely to have changed significantly. 
5.2.2
Subsequent Cycles 
Treatment may proceed if the following criteria are met: 
 ECOG performance status of 2 or less 
 No evidence of life-threatening medical problems
 Criteria for dose modification or hold of study-specific medications should be 
followed, per Section 6 
5.2.3
Criteria to Re-challenge 
Patients who elect to stop treatment with Nivolumab after 2 years of therapy (as outlined in 
Section 5.5) and subsequently progress can be re-challenged if they meet the following selected 
eligibility criteria:

Laboratory values defined in section 3.1.13.

No interim diagnosed malignancy as defined in section 3.1.14.

No interim systemic therapy. (Interim palliative radiation for selective 
supplemental treatment may be allowed after discussion with the Overall PI.)

Patients with brain metastases must meet criterion 3.2.7.

Patients must also meet eligibility criteria as defined in sections 3.1.16, 3.1.17, 
and 3.1.18 and exclusion criteria as defined in sections 3.2.5, 3.2.8, 3.2.10, 3.2.11, 
3.2.12, and 3.2.13.

Patients must be reconsented to any consent form changes during the interim.
For patients who elected to also stop Bevacizumab (Cohort 1) or Bevacizumab/Rucaparib 
(Cohort 2 or Cohort 3) at the time of stopping treatment Nivolumab who wish to be re-
challenged may not have had any interim events meeting exclusion criteria defined in section 
3.2.21.
Patients who discontinue therapy due to disease progression or adverse events may not be re-
challenged.
5.3
Agent Administration
5.3.1
Nivolumab Administration
Nivolumab is to be administered as a 30-minute (± 10 minute) IV infusion. For details on 
prepared drug storage, preparation, and administration, please refer to the Nivolumab 
Investigator Brochure (IB).
Nivolumab injection is to be administered as an IV infusion through a 0.2-micron to 1.2-micron 
pore size, low-protein binding polyethersulfone membrane in-line filter at 240 mg. It is not to be 
administered as an IV push or bolus injection. Nivolumab injection will be infused diluted with 
0.9% Sodium Chloride Injection, USP or 5% Dextrose Injection, USP to protein concentrations as 
low as 0.35 mg/mL. The total infusion volume should not exceed 120 mL. Care must be taken to 

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assure sterility of the prepared solution as the product does not contain any antimicrobial 
preservative or bacteriostatic agent. 
5.3.2
Bevacizumab Administration
Bevacizumab will be given at 10 mg/kg in 100 cc NS, with dosing weight calculated by actual 
body weight or per institutional standards. It should be given intravenously over 30 minutes, 
though infusion duration may vary per institutional guidelines. Bevacizumab will be given 30 
(+/- 10) minutes after conclusion of nivolumab infusion. 
For details on prepared drug storage, preparation, and administration, please refer to the 
Bevacizumab Investigator Brochure (IB) and/or pharmacy reference sheets.
5.3.3
Rucaparib Administration
Rucaparib should be taken orally twice daily 12 hours apart with or without food. Rucaparib 
cannot be chewed, crushed or dissolved. If a dose of rucaparib is missed by more than four hours 
from the scheduled time, the participant should omit that dose and take the next dose at its 
scheduled time.  Vomited doses should not be replaced.
5.4
General Concomitant Medication and Supportive Care Guidelines
5.4.1
Prohibited treatments
The following medications are prohibited during the study: 
 Immunosuppressive agents (except to treat a drug-related adverse event) 
 Systemic corticosteroids > 10 mg daily prednisone equivalent (except as noted in
  Section 3.2.17  and 5.4.2, or to treat a drug-related adverse event). 
 Any concurrent antineoplastic therapy (i.e., chemotherapy, hormonal therapy,
immunotherapy, radiation therapy except for palliative radiation therapy, or 
standard or investigational agents for treatment of cancer) or natural herbal products 
or other “folk remedies”. Supportive care for disease-related symptoms may be 
offered to all subjects on the trial.
5.4.2
Permitted therapy
Subjects are permitted to use topical, ocular, intra-articular, intranasal, and inhalational 
corticosteroids (with minimal systemic absorption). A brief course of corticosteroids for 
prophylaxis (e.g., contrast dye allergy) or for treatment of non-autoimmune conditions (e.g., 
delayed-type hypersensitivity reaction caused by contact allergen) is permitted. 
Concomitant medications are recorded at baseline and throughout the treatment phase of the 
study in the appropriate section of the case report form (CRF). All medications (prescriptions or 

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over the counter medications) continued at the start of the study or started during the study and 
different from the study drug must be documented in the concomitant therapy section of the 
CRF.
5.5
Criteria for Taking a Participant Off Protocol Therapy
Duration of therapy will depend on individual response, evidence of disease progression and 
tolerance. In the absence of treatment delays due to adverse event(s), treatment may continue 
indefinitely or until one of the following criteria applies:

Disease progression

Intercurrent illness that prevents further administration of treatment

Unacceptable adverse event(s)

Participant demonstrates an inability or unwillingness to comply with the oral 
medication regimen and/or documentation requirements

Participant decides to withdraw from the protocol therapy

General or specific changes in the participant's condition render the participant 
unacceptable for further treatment in the judgment of the treating investigator

Participant has completed 2 years of treatment with nivolumab (treatment may 
continue beyond 2 years per investigator and participant discretion). Participant may 
continue on bevacizumab alone (Cohort 1) or bevacizumab/rucaparib (Cohort 2 or 
Cohort 3) per investigator discretion should nivolumab be stopped. (Note: If the 
patient subsequently progresses re-challenge is allowed after discussion with the 
Overall PI, please see section 5.2.3 for re-challenge criteria.) 
Participants will be removed from the protocol therapy when any of these criteria apply.  The 
reason for removal from protocol therapy, and the date the participant was removed, must be 
documented in the case report form (CRF). Alternative care options will be discussed with the 
participant.
When a participant is removed from protocol therapy and/or is off of the study, the relevant Off-
Treatment/Off-Study information will be updated in OnCore.
In December 2022, Clovis Oncology communicated that, due to financial considerations and 
bankruptcy filing, they will not be able to provide the study agent rucaparib for use in this study 
beyond the supply currently available and allocated for this study.  Participants in Cohorts 2 and 
3 who are receiving rucaparib may therefore no longer be able to continue on rucaparib once this 
available rucaparib supply has been exhausted.  Participants affected by this drug supply issue 
will be able to continue study treatment with nivolumab and/or bevacizumab following rucaparib 
discontinuation per investigator and participant discretion.

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In the event of unusual or life-threatening complications, treating investigators must immediately 
notify the Overall PI, Joyce Liu at 
 
5.6
Duration of Follow Up
After removal from protocol therapy, participants will be followed until death.
5.7
Criteria for Taking a Participant Off Study
Participants will be removed from study when any of the following criteria apply:

Lost to follow-up

Withdrawal of consent for data submission

Death
The reason for taking a participant off study, and the date the participant was removed, must be 
documented in the case report form (CRF). In addition, the study team will ensure Off 
Treatment/Off Study information is updated in OnCore in accordance with DF/HCC policy 
REGIST-101.
5.8
Treatment Beyond Disease Progression
Accumulating evidence indicates that a minority of subjects treated with immunotherapy may 
derive clinical benefit despite initial evidence of progressive disease (PD). Subjects treated with 
nivolumab will be permitted to continue treatment beyond initial PD as assessed by the 
investigator’s clinical judgment and local standards of care as long as they meet the following 
criteria: 

Investigator-assessed clinical benefit and do not have rapid disease progression 

Tolerance of study drug 

Stable performance status 

Treatment beyond progression will not delay an imminent intervention to prevent serious 
complications of disease progression (e.g., CNS metastases) 
The assessment of clinical benefit should take into account whether the subject is clinically 
deteriorating and unlikely to receive further benefit from continued treatment. 
All decisions to continue treatment beyond initial progression must be discussed with the overall 
principal investigator. Subjects will be re-consented with an ICF describing any reasonably 
foreseeable risks or discomforts. Decisions to continue treatment beyond initial progression will 
be documented in the study records.
A radiographic assessment/ scan should be performed within 6 weeks of initial investigator-
assessed progression to determine whether there has been a decrease in the tumor size or continued 
PD. The assessment of clinical benefit should be balanced by clinical judgment as to whether the 
subject is clinically deteriorating and unlikely to receive any benefit from continued treatment with 
combination nivolumab and bevacizumab.

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For the subjects who continue on study therapy beyond progression, further progression is defined 
as an additional 10% increase in tumor burden from time of initial PD. This includes an increase 
in the sum of diameters of all target lesions and/ or the diameters of new measurable lesions 
compared to the time of initial PD. Study treatment should be discontinued permanently upon 
documentation of further progression.
New lesions are considered measureable at the time of initial progression if the longest diameter 
is at least 10 mm (except for pathological lymph nodes which must have a short axis of at least15 
mm). Any new lesion considered non-measureable at the time of initial progression may become 
measureable and therefore included in the tumor burden if the longest diameter increases to at least 
10 mm (except for pathological lymph nodes which must have a short axis of at least 15 mm). In 
situations where the relative increase in total tumor burden by 10% is solely due to inclusion of 
new lesions which become measurable, these new lesions must demonstrate an absolute increase 
of at least 5 mm.
For statistical analyses, this will need to be described in patient population information. (e.g. 
subjects who continue treatment beyond initial investigator-assessed, RECIST 1.1-defined 
progression will be considered to have investigator-assessed progressive disease at the time of 
the initial progression event as these immune responses may be used in determining 
advancement to the second stage).
6.
DOSING DELAYS/DOSE MODIFICATIONS
Dose delays and modifications will be made as indicated in the following table(s). The 
descriptions and grading scales found in the revised NCI Common Terminology Criteria for 
Adverse Events (CTCAE) version 4.0 will be utilized for dose delays and dose modifications. A 
copy of the CTCAE version 4.0 can be downloaded from the CTEP website
 http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm. 
Dose holds and modifications can be made separately for each study medication (nivolumab, 
bevacizumab, or rucaparib), depending upon the observed adverse event and the attribution.  
Dose holds can be made independently for each study medication surrounding clinical 
procedures (e.g. port placement) as appropriate per standard of care guidelines.  Dose holds may 
also be made at the discretion of the treating physician with the approval of the overall PI if 
clinically indicated for medical reasons other those described in this section.  For patients in 
Cohort 2 and Cohort 3, cycles are numbered continuously with each cycle being 14 days in 
length; rucaparib dosing may be re-initiated mid-cycle, but bevacizumab and nivolumab dosing 
should occur/be resumed on day 1 of each cycle only.
6.1
Nivolumab Dose Modifications
Nivolumab dose reductions or dose escalations are not permitted. When blood counts have 
recovered or toxicities have resolved as described in section 6.3 and 6.8, nivolumab will be 
resumed at full dose. 

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6.2
Bevacizumab Dose Modifications
Bevacizumab dose escalations are not permitted. One dose reduction is permitted:
Dose Level
Bevacizumab Dose
0
10 mg/kg every 2 weeks
-1
5 mg/kg every 2 weeks

All dose reductions are permanent.

A maximum of 1 dose bevacizumab reduction is possible. Patients requiring more than 1 
dose reduction must discontinue study treatment.  Patients who are deriving clinical 
benefit and experience bevacizumab-related toxicities necessitating discontinuation of 
bevacizumab may be allowed to continue on nivolumab alone (or combination 
nivolumab/rucaparib for patients in Cohort 2 or Cohort 3) after discussion with the study 
PI.

If patients have not recovered blood counts or resolved toxicities to required levels within 
6 weeks, patients must discontinue study treatment.
6.3
Rucaparib Dose Modifications
Cohorts 1 and 2:  Dose reductions of rucaparib are permitted, as per the table below.  The dose of 
rucaparib should not be lowered below 300mg twice daily.
Dose Level
Rucaparib Dose
0
600mg twice daily
-1
500mg twice daily
-2
400mg twice daily
-3
300mg twice daily
Cohort 3:  Dose reduction of rucaparib is permitted, as per the table below.
Dose Level
Rucaparib Dose
0
300mg twice daily*
-1
200mg twice daily*
*A dose level of 250mg twice daily may be implemented for select patients as described in the 
following paragraphs.
For select patients who have not experienced significant adverse events after receiving 
combination nivolumab, bevacizumab, and rucaparib for at least 100 days, dose escalation of 
rucaparib to 400mg twice daily may be considered in the setting of stable disease or disease 
progression after discussion with the overall Study PI.
As communicated by Clovis Oncology in December 2022, available supply of rucaparib 200mg 
tablets for this study is no longer available outside of supply already distributed to the 
participating study sites.  Additionally, all available 300mg tablets for this study will expire in 
March of 2023.  A significant supply of 250mg tablets is available that will expire in January of 

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2024.  No other tablet sizes are available for distribution for this study.  Because of these drug 
availability issues, additional considerations to the dose reductions and modifications for 
rucaparib include:

For patients receiving rucaparib 300mg twice daily requiring a dose reduction after 
January 10, 2023, patients should be dose reduced to 250mg twice daily.  Patients who 
require dose reduction beyond 250mg twice daily will need to be discontinued from 
rucaparib therapy. At the discretion of the treating investigator and the patient, patients 
receiving rucaparib 300mg twice daily will have the option of continuing on rucaparib at 
250mg twice daily or discontinuing rucaparib therapy when the supply of rucaparib 
300mg tablets is exhausted.

Patients receiving rucaparib 200mg twice daily after January 10, 2023 may continue on 
rucaparib 200mg twice daily dosing until drug supply of 200mg tablets are exhausted.  At 
the discretion of the treating investigator and the patient, patients who are deriving 
clinical benefit and tolerating rucaparib 200mg twice daily well have the option of either 
dose escalation of rucaparib to 250mg twice daily or discontinuing rucaparib therapy 
when the supply of rucaparib 200mg tablets is exhausted.
6.3.1
Hematologic toxicity
Patients experiencing hematologic toxicities related to rucaparib should be managed by the 
following table.  Use of hematopoietic agents is not allowed on trial.
Table 6.3.1:  Dose Modification and Management of Hematologic Adverse Events
Hematologic Event
Dose Modification
Absolute neutrophil count ≥ 1000/mcL
AND 
Platelets ≥ 100,000/mcL
AND
Hemoglobin ≥ 8 mg/dL 
Maintain dose level
Absolute neutrophil count < 1000/mcL
OR
Platelets < 100,000/mcL
OR
Hemoglobin < 8 mg/dL
Hold treatment until absolute neutrophil count ≥ 
1000/mcL, platelets ≥ 100,000/mcL, and 
hemoglobin ≥ 8 mg/dL. Treatment may be restarted 
at one dose level lower.
Patients whose counts have not recovered to 
absolute neutrophil count ≥ 1000/mcL, platelets ≥ 
100,000/mcL, and hemoglobin ≥ 8 mg/dL within 28 
days should be discontinued from rucaparib.
Grade 4 hematologic AE related to rucaparib that 
does not resolve to absolute neutrophil count ≥ 
1000/mcL, platelets ≥ 100,000/mcL, and 
hemoglobin ≥ 8 mg/dL despite maximum 
supportive care after 28 days.
Permanently discontinue rucaparib.
Patients who have treatment held for hematologic toxicities should have blood counts and 
differentials checked at least weekly until recovery. If counts do not improve to CTCAE grade 1 
or better despite drug cessation for 4 weeks, patients should be referred to a hematologist for 

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further assessment.  A bone marrow analysis should be considered per hematology assessment.
6.3.2
Non-hematologic toxicity
Patients experiencing non-hematologic toxicities related to rucaparib should be managed by the 
following table.  Guidelines for management of AST/ALT elevations are provided separately in 
Section 6.3.3, and should be followed instead of the table below.
6.3.3
AST/ALT elevation (Cohorts 2 and 3 only)
ALT/AST elevations have been observed with rucaparib, and are also a potential side effect of 
nivolumab.  Rucaparib-mediated elevations in ALT/AST (without accompanying rise in 
bilirubin) can be observed to start within 15 days of starting drug, and may subsequently 
spontaneously improve even in the setting of continued rucaparib therapy.  For patients on cohort 
2 or cohort 3 who experience an ALT/AST elevation, management should be as follows.  For 
patients who have discontinued bevacizumab therapy for other reasons, rechallenge may occur 
with rucaparib monotherapy.  (Please note that, as cycles are counted continuously, 
rechallenging with rucaparib/bevacizumab may result in initiating rucaparib therapy mid-cycle 
and subsequently treating with bevacizumab on Day 1 of the subsequent cycle):
Table 6.3.2:  General Management of Rucaparib-related Non-Hematologic Toxicity
Observation
Action
AE resolves promptly with supportive care 
Maintain dose level
Any   grade 3 non-hematologic (excluding grade 3 
fatigue or easily correctable asymptomatic grade 3 
laboratory abnormalities)
Hold rucaparib until toxicity resolves to  grade 
1. Treatment may be restarted at one dose level 
lower1. If symptoms do not resolve to  grade 1 
within 28 days, rucaparib should be 
discontinued.
Any grade 2 non-hematologic AE or grade 3 fatigue 
that persists despite maximal support. 
Hold rucaparib until toxicity resolves to  grade 
1.  Treatment may be restarted at either the same 
dose or one dose level lower, per investigator 
discretion1.  If symptoms do not resolve to  
grade 1 within 28 days, rucaparib should be 
discontinued.
1. Grade 3 or 4 non-hematologic AE that does not 
resolve to grade 0-2 within 28 days despite 
maximum supportive care after treating patient at 
the lowest reduced dose level.2
2. Grade 3 or 4 non-hematologic AE lasting > 28 
days despite maximum supportive care and 
treatment being held.
Permanently discontinue rucaparib.
1Patients who are at the lowest reduced dose level may have their drug resumed at that dose level after 
discussion with the Study Chair if evidence of clinical benefit.
2For thromboembolic events, treatment may be resumed at the discretion of the investigator once patient 
is asymptomatic.  For weight loss events, treatment may be resumed or continued at the discretion of 
the investigator if the weight stabilizes after an initial weight loss.

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
Grade 4 ALT/AST elevation:  
o
If accompanied by elevation in bilirubin, discontinue from study and initiate 
management of potential immune-related hepatitis as clinically appropriate.
o
If no accompanying elevation in bilirubin, hold study drugs and initiate 
management of potential immune-related hepatitis as clinically appropriate.  
Monitor liver enzymes every 2-3 days.  If immune-related hepatitis is not 
suspected and transaminases resolve spontaneously to grade 1 or better without 
empiric or other therapy directed towards immune-related hepatitis, rechallenge 
with rucaparib at the next lower dose level together with bevacizumab may be 
considered after discussion with the overall PI.  Nivolumab may not be re-
instituted until combination rucaparib/bevacizumab has been received for at least 
2 weeks and ALT/AST levels remain Grade 1 or better.  In select patients whose 
ALT/AST levels remain stable or improved at Grade 2 after at least 4 weeks of 
rucaparib/bevacizumab dosing, re-initiation of nivolumab may be considered after 
discussion with the PI.

Grade 3 ALT/AST elevation:
o
ALT/AST > 8x ULN:  Manage per Grade 4 ALT/AST elevation.
o
ALT/AST ≤ 8x ULN with rise in bilirubin above ULN:  Hold study treatment and 
monitor liver enzymes every 2 to 3 days.  If ALT/AST elevation increases to >8x 
ULN, discontinue from study and initiate management of potential immune-
related hepatitis as clinically appropriate.  If ALT/AST resolves to Grade 2, 
rucaparib and bevacizumab dosing may be resumed at the ongoing dose or with a 
dose reduction in rucaparib, per investigator discretion, with liver enzymes being 
monitored every 3 days.  Nivolumab dosing should not be resumed until 
ALT/AST resolve to Grade 1 or better. Select patients whose ALT/AST 
elevations resolve to Grade 2 and have improving but persistent Grade 2 
ALT/AST levels for at least 2 weeks on rucaparib/bevacizumab may be 
considered for resumption of nivolumab dosing after discussion with the PI.
o
ALT/AST ≤ 8x ULN without accompanying rise in bilirubin:  Hold nivolumab 
and monitor liver enzymes every 2 to 3 days.  Rucaparib and bevacizumab dosing 
may be continued.  If ALT/AST rise above 8x ULN, manage per Grade 4 
ALT/AST elevation.  Nivolumab dosing should not be resumed until ALT/AST 
resolve to Grade 1 or better. Select patients whose ALT/AST elevations resolve to 
Grade 2 and have improving but persistent Grade 2 ALT/AST levels for at least 2 
weeks on rucaparib/bevacizumab may be considered for resumption of nivolumab 
dosing after discussion with the PI.

Grade 2 ALT/AST elevation:
o
Hold nivolumab and monitor liver enzymes every 2 to 3 days.  Rucaparib and 
bevacizumab dosing may be continued.  Nivolumab dosing may be resumed once 
ALT/AST resolve to Grade 1 or better. Select patients whose ALT/AST remain at 
Grade 2 and are improving numerically for at least 2 weeks on 
rucaparib/bevacizumab may be considered for resumption of nivolumab dosing 
after discussion with the PI.

Grade 1 ALT/AST elevation
o
Continue study treatment and monitor liver enzymes per study protocol.

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6.3.4
Cholesterol elevation
Cholesterol elevations to Grade 3 or higher have been observed with rucaparib.  Patients 
experiencing elevation in cholesterol may be started on an HMG-CoA reductase inhibitor 
(commonly known as a statin) as clinically appropriate.  Please refer to Section 8.3.8 regarding 
drug-drug interactions and statins.
Patients experiencing a Grade 3 or higher cholesterol elevation should have rucaparib held and 
should initiate treatment with a statin if not already initiated, or have adjustments made to their 
cholesterol management regimen if a statin has already been initiated.  Dosing may resume at the 
same or a reduced dose of rucaparib, per the investigator’s discretion once cholesterol elevation 
has resolved to Grade 2 or better. 
6.4
Treatment Modification for Nivolumab-Related Adverse Events
Because of the potential for clinically meaningful nivolumab-related AEs requiring early 
recognition and prompt intervention, management algorithms have been developed for suspected 
AEs of selected categories. See Investigator Brochure and Appendix B for management 
algorithms. 
Of note, treatment with nivolumab dosing should be delayed for the following:

Any Grade ≥ 2 non-skin, drug-related AE, with the following exceptions:
o
Grade 2 drug-related fatigue or laboratory abnormalities do not require a 
treatment delay
o
Patients in Cohort 2 and Cohort 3 receiving concomitant rucaparib who 
experience a Grade 2 elevation in serum creatinine that is not accompanied by 
elevation in BUN may continue with nivolumab and bevacizumab with close 
interval monitoring of serum creatinine.  Patients who experience a Grade 2 
elevation in serum creatinine that has demonstrated close concordance with 
rucaparib administration (resolution with rucaparib hold and recurrent elevation 
with rucaparib resumption) may also be continued on nivolumab and 
bevacizumab.

Any Grade 3 skin, nivolumab-related AE

Any Grade 3 nivolumab-related laboratory abnormality, with the following exceptions 
for lymphopenia, leukopenia, AST, ALT, total bilirubin, or asymptomatic amylase or 
lipase:
o
Grade 3 lymphopenia or leukopenia does not require dose delay.
o
For patients receiving nivolumab and bevacizumab alone, if a subject has a 
baseline AST, ALT, or total bilirubin that is within normal limits, delay dosing for 
drug-related Grade ≥ 2 toxicity.  For patients receiving combination nivolumab, 
bevacizumab, and rucaparib, please see Section 6.3.3 for further details regarding 
management.
o
For patients receiving nivolumab and bevacizumab alone, if a subject has baseline 
AST, ALT, or total bilirubin within the Grade 1 toxicity range, delay dosing for 
drug-related Grade ≥ 3 toxicity.  For patients receiving combination nivolumab, 

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bevacizumab, and rucaparib, please see Section 6.3.3 for further details regarding 
management.
o
Any Grade ≥ 3 drug-related amylase or lipase abnormality that is not associated 
with symptoms or clinical manifestations of pancreatitis does not require dose 
delay. The investigator should be consulted for such Grade ≥ 3 amylase or lipase 
abnormalities. 
o
Patients in cohort 2 and cohort 3 experiencing Grade 3 or higher cholesterol 
elevation attributed to rucaparib alone may continue with nivolumab and 
bevacizumab dosing.  Rucaparib dosing should be managed as per Section 6.3.4.

Any AE, laboratory abnormality, or intercurrent illness which, in the judgment of the 
investigator, warrants delaying the dose of study medication.
Subjects who require delay should be re-evaluated weekly or more frequently if clinically 
indicated and resume nivolumab dosing when re-treatment criteria are met.
6.5
Criteria to Resume Treatment Following Nivolumab-Related Adverse Events
Subjects may resume treatment with nivolumab when the drug-related AE(s) resolve to Grade ≤1 
or baseline value, with the following exceptions:

Subjects may resume treatment in the presence of Grade 2 fatigue 

Subjects who have not experienced a Grade 3 drug-related skin AE may resume 
treatment in the presence of Grade 2 skin toxicity 

For subjects in Cohorts 2 or 3 with AST/ALT elevation, nivolumab dosing may be 
resumed as per Section 6.3.3.

For subjects in Cohort 1:
o
Subjects with baseline Grade 1 AST/ALT or total bilirubin who require dose 
delays for reasons other than a 2-grade shift in AST/ALT or total bilirubin may 
resume treatment in the presence of Grade 2 AST/ALT OR total bilirubin
o
Subjects with combined Grade 2 AST/ALT AND total bilirubin values meeting 
discontinuation parameters should have treatment permanently discontinued

Drug-related pulmonary toxicity, diarrhea, or colitis, must have resolved to baseline 
before treatment is resumed. Subjects with persistent Grade 1 pneumonitis after 
completion of a steroid taper over at least 1 month may be eligible for retreatment after 
discussion with and approval from the principal investigator. 

Drug-related endocrinopathies adequately controlled with only physiologic hormone 
replacement may resume treatment after discussion with and approval from the principal 
investigator.
If treatment is delayed or interrupted for >6 weeks, the subject must be permanently discontinued 
from nivolumab therapy. Dosing delays or interruptions to allow for prolonged steroid tapers to 
manage drug-related adverse events are allowed. Prior to re-initiating treatment in a subject with 
a dosing interruption lasting > 6 weeks, the PI must be consulted. Patients who are clinically 
benefitting from study treatment who require dose interruption for >6 weeks may be considered 
for continuation for resumption of nivolumab treatment after discussion with the study PI. 

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6.6
Nivolumab Management Algorithms
Immuno-oncology (I-O) agents are associated with AEs that can differ in severity and duration 
than AEs caused by other therapeutic classes. Nivolumab is considered an immuno-oncology 
agent in this protocol. Early recognition and management of AEs associated with immuno-
oncology agents may mitigate severe toxicity. Management algorithms have been developed to 
assist investigators in assessing and managing the following groups of AEs:
Gastrointestinal, Renal, Pulmonary, Hepatic, Endocrinopathies, Skin, Neurological.
For subjects expected to require more than 4 weeks of corticosteroids or other 
immunosuppressants to manage an AE, consider recommendations provided in the algorithms. 
These algorithms are found in the nivolumab IB and in Appendix B of this protocol. The 
guidance provided in these algorithms should not replace the Investigator’s medical judgment 
but should complement it.
6.7
Treatment Discontinuation Criteria for Nivolumab-Related Adverse Events
Treatment should be permanently discontinued for the following:

Any Grade 2 drug-related uveitis or eye pain or blurred vision that does not respond to 
topical therapy and does not improve to Grade 1 severity within the re-treatment period 
OR requires systemic treatment 

Any Grade 3 non-skin, drug-related adverse event lasting > 7 days, with the following 
exceptions for drug-related laboratory abnormalities, uveitis, pneumonitis, 
bronchospasm, hypersensitivity reactions, and infusion reactions, and endocrinopathies:
o
Grade 3 drug-related uveitis, pneumonitis, bronchospasm, hypersensitivity 
reaction, or infusion reaction of any duration requires discontinuation
o
Grade 3 drug-related endocrinopathies adequately controlled with only 
physiologic hormone replacement do not require discontinuation

Grade 3 drug-related laboratory abnormalities do not require treatment discontinuation 
except those noted below:
o
Grade 3 drug-related thrombocytopenia >7 days or associated with bleeding 
requires discontinuation
o
For patients in Cohort 1:  Any drug-related liver function test (LFT) abnormality 
that meets the following criteria require discontinuation: 
•
AST or ALT > 5 x ULN
•
Total bilirubin > 3 x ULN
•
Concurrent AST or ALT > 3 x ULN and total bilirubin > 2 x ULN
•
For patients in Cohort 2 and Cohort 3, management of LFT abnormalities 
should be as per Section 6.3.3.

Any Grade 4 drug-related adverse event or laboratory abnormality, except for the 
following events which do not require discontinuation:
o
Isolated Grade 4 amylase or lipase abnormalities that are not associated with 
symptoms or clinical manifestations of pancreatitis 
o
Isolated Grade 4 electrolyte imbalances/abnormalities that are not associated with 
clinical sequelae and are corrected with supplementation/appropriate management 
within 72 hours of their onset

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o
Grade 4 lymphopenia or leucopenia
o
Grade 4 drug-related endocrinopathy adverse events, such as adrenal 
insufficiency, ACTH deficiency, hyper- or hypothyroidism, or glucose 
intolerance, which resolve or are adequately controlled with physiologic hormone 
replacement (corticosteroids, thyroid hormones) or glucose-controlling agents, 
respectively after discussion with and approval from the principal investigator. 
o
For patients in Cohort 2 and Cohort 3:  Grade 4 ALT/AST abnormalities without 
accompanying bilirubin abnormality that are attributed to rucaparib alone and 
spontaneously resolve without treatment for immune-related hepatitis, as outlined 
in Section 6.3.3.

Any dosing interruption lasting > 6 weeks with the following exceptions:
o
Dosing delays or interruptions to allow for prolonged steroid tapers to manage 
drug-related adverse events are allowed. Prior to re-initiating treatment in a 
subject with a dosing interruption lasting > 6 weeks, the PI must be consulted. 
Tumor assessments should continue as per protocol even if dosing is interrupted 
or delayed
o
Dosing interruptions or delays lasting > 6 weeks that occur for non-drug-related 
reasons may be allowed if approved by the Investigator. Prior to re-initiating 
treatment in a subject with a dosing interruption lasting > 6 weeks, the PI must be 
consulted. Tumor assessments should continue as per protocol even if dosing is 
interrupted
o
Any adverse event, laboratory abnormality, or intercurrent illness which, in the  
judgment of the PI, presents a substantial clinical risk to the subject with 
continued nivolumab dosing
6.8
Treatment of Nivolumab Related Infusion Reactions
Since nivolumab contains only human immunoglobulin protein sequences, it is unlikely to be 
immunogenic and induce infusion or hypersensitivity reactions. However, if such a reaction were 
to occur, it might manifest with fever, chills, rigors, headache, rash, pruritus, arthralgias, hypo- or 
hypertension, bronchospasm, or other symptoms of allergic-like reactions. 
All Grade 3 or 4 infusion reactions should be reported as an SAE if criteria are met. Infusion 
reactions should be graded according to NCI CTCAE 4.0 guidelines.
Treatment recommendations are provided below and may be modified based on local treatment 
standards and guidelines as appropriate:
For Grade 1 symptoms: (Mild reaction; infusion interruption not indicated; intervention not 
indicated)
Remain at bedside and monitor subject until recovery from symptoms. The following prophylactic 
premedications are recommended for future infusions: diphenhydramine 50 mg (or equivalent) 
and/or acetaminophen 325 to 1000 mg at least 30 minutes before additional nivolumab 
administrations.

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For Grade 2 symptoms: (Moderate reaction requires therapy or infusion interruption but responds 
promptly to symptomatic treatment [e.g., antihistamines, non-steroidal anti-inflammatory drugs, 
narcotics, corticosteroids, bronchodilators, IV fluids]; prophylactic medications indicated for 24 
hours).
Stop the nivolumab infusion, begin an IV infusion of normal saline, and treat the subject with 
diphenhydramine 50 mg IV (or equivalent) and/or acetaminophen 325 to 1000 mg; remain at 
bedside and monitor subject until resolution of symptoms. Corticosteroid or bronchodilator 
therapy may also be administered as appropriate. If the infusion is interrupted, then restart the 
infusion at 50% of the original infusion rate when symptoms resolve; if no further complications 
ensue after 30 minutes, the rate may be increased to 100% of the original infusion rate. Monitor 
subject closely. If symptoms recur then no further nivolumab will be administered at that visit. 
Administer diphenhydramine 50 mg IV, and remain at bedside and monitor the subject until 
resolution of symptoms. The amount of study drug infused must be recorded on the electronic case 
report form (eCRF). The following prophylactic premedications are recommended for future 
infusions: diphenhydramine 50 mg (or equivalent) and/or acetaminophen 325 to 1000 mg should 
be administered at least 30 minutes before additional nivolumab administrations. If necessary, 
corticosteroids (recommended dose: up to 25 mg of IV hydrocortisone or equivalent) may be used.
For Grade 3 or Grade 4 symptoms: (Severe reaction, Grade 3: prolonged [i.e., not rapidly 
responsive to symptomatic medication and/or brief interruption of infusion]; recurrence of 
symptoms following initial improvement; hospitalization indicated for other clinical sequelae 
[e.g., renal impairment, pulmonary infiltrates]). Grade 4: (life threatening; pressor or ventilatory 
support indicated). 
Immediately discontinue infusion of nivolumab. Begin an IV infusion of normal saline, and treat 
the subject as follows. Recommend bronchodilators, epinephrine 0.2 to 1 mg of a 1:1,000 solution 
for subcutaneous administration or 0.1 to 0.25 mg of a 1:10,000 solution injected slowly for IV 
administration, and/or diphenhydramine 50 mg IV with methylprednisolone 100 mg IV (or 
equivalent), as needed. Subject should be monitored until the investigator is comfortable that the 
symptoms will not recur. Nivolumab will be permanently discontinued. Investigators should 
follow their institutional guidelines for the treatment of anaphylaxis. Remain at bedside and 
monitor subject until recovery from symptoms. 
In the case of late-occurring hypersensitivity symptoms (e.g., appearance of a localized or 
generalized pruritus within 1 week after treatment), symptomatic treatment may be given (e.g., 
oral antihistamine, or corticosteroids).
6.9
Treatment Modification for Bevacizumab-Related Adverse Events
Event
CTCAE 
Version 4 
Grade
Action to be Taken

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Grade 1-2

Infusion of bevacizumab should be interrupted 
for subjects who develop dyspnea or clinically 
significant hypotension.

For infusion-associated symptoms not specified 
above, infusion should be slowed to 50% or less 
or interrupted. Upon complete resolution of the 
symptoms, infusion may be continued at no 
more than 50% of the rate prior to the reaction 
and increased in 50% increments every 30 
minutes if well tolerated. Infusions may be 
restarted at the full rate during the next cycle.

Subjects who experience bronchospasm 
(regardless of grade) should discontinue therapy.
Allergic reactions, 
Infusion-related 
reactions, or 
Anaphylaxis
Grade 3-4

Discontinue therapy
Thromboembolic Event 
(Arterial); arterial 
ischemia
   -Cardiac ischemia
   -Myocardia 
infraction
   -CNS ischemia (TIA, 
CVA)
   -Any peripheral or
     visceral arterial
     ischemia/thrombosis
Grade 2-4

Discontinue Therapy
Thromboembolic Event 
(Venous)
Grade 3 or 
asymptomatic 
Grade 4

Hold treatment of both bevacizumab and 
nivolumab. If the planned duration of full-dose 
anticoagulation is ≤ 2 weeks, treatment should 
be held until the full-dose anticoagulation period 
is over.

If the planned duration of full-dose 
anticoagulation is > 2 weeks, treatment may be 
resumed with bevacizumab during full-dose 
anticoagulation if all of the following criteria are 
met:
          -The subject must not have pathological
            conditions that carry high risk of bleeding 
(e.g. 
            tumor involving major vessels or other
            conditions)
          -The subject must not have had hemorrhagic
            events while on study
          -The subject must be on a stable 
anticoagulation regimen prior to restarting 

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            treatment.

If thromboemboli worsen/recur upon resumption 
of study therapy, discontinue treatment.
Symptomatic 
Grade 4

Discontinue therapy.
Grade 1 (SBP 
120-139 
mmHg or 
DBP80-89 
mmHg)

Consider increased BP monitoring and start anti-
hypertensive medication if appropriate.
Grade 2 
asymptomatic 
(SBP 140-
159 mmHg or 
DBP 90-99 
mm Hg)

Begin anti-hypertensive therapy and continue 
treatment. 
Grade 2 
symptomatic 
(SBP 140-
160 mmHg or 
DBP 90-100 
mm Hg) 
Grade 3 (≥ 
SBP 160 
mmHg or ≥ 
DBP 100 
mmHg)

Start or adjust anti-hypertensive medication

Hold treatment until symptoms resolve AND BP 
< 160/90mmHg. 

For HTN that is refractory requiring delay of > 6 
weeks, discontinue treatment.
Hypertension
Grade 4 
(Hypertensive 
crisis or 
malignant 
hypertension)

Discontinue treatment. 
Heart Failure or LV 
dysfunction
Grade 3 or 4

Discontinue treatment. 
If UPC < 2.0 

Continue treatment.
If UPC ≥ 2.0

Hold treatment until UPC < 2.0

Discontinue treatment if UPC does not recover 
to < 2.0 after 6 weeks of treatment interruption.
Proteinuria
(Proteinuria should be 
monitored by dipstick 
prior to every dose of 
bevacizumab. If 
dipstick ≥ 2+ 
proteinuria, urine 
protein:creatinine 
(UPC) ratio should be 
obtained)
Nephrotic 
syndrome

Remove from treatment.

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Grade 1

Patients receiving full-dose anticoagulation 
should be removed from study.

For patients not on full-dose anticoagulation, 
hold treatment until ALL of the following 
criteria are met:
   -the bleeding has resolved and Hb is stable
   -there is no bleeding diathesis that would 
    increase the risk of therapy
         -there is no anatomic or pathologic condition
          that could increase the risk of hemorrhage 
          recurrence
Hemorrhage 
(intracranial or 
pulmonary)
Grade 2-4

Discontinue treatment
Grade 3

Patients receiving full-dose anticoagulation 
should be removed from study.

For patients not on full-dose anticoagulation, 
hold treatment until ALL of the following 
criteria are met:
   -the bleeding has resolved and Hb is stable
   -there is no bleeding diathesis that would 
    increase the risk of therapy
         -there is no anatomic or pathologic condition
          that could increase the risk of hemorrhage 
          recurrence

Patients who experience recurrence of grade 3 
hemorrhage should discontinue treatment.
Hemorrhage (any other 
organ systems)
Grade 4

Discontinue treatment.
RPLS (Reversible Posterior 
Leukoencephalopathy syndrome) or 
PRES (Posterior Reversible 
Encephalopathy Syndrome)

Discontinue treatment. 
Wound dehiscence requiring medical 
or surgical intervention

Discontinue treatment. 
Perforation (GI, or any other organ)

Discontinue treatment. 
Fistula (GI, pulmonary, or any other 
organ)

Discontinue treatment. 
Grade 2 
requiring 
medical 
intervention

Hold treatment until complete resolution.
Obstruction of GI tract
Grade 3 and 4

Hold treatment until complete resolution. 

If surgery is required, patient should be 
discontinued from study therapy.
Other unspecified 
bevacizumab-related 
Grade 3

Hold treatment until symptoms resolve to ≤ 
grade 1. 

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AEs (except controlled 
nausea/vomiting).
Grade 4

Discontinue treatment. 

Upon consultation with the overall principal 
investigator, resumption of study treatment if 
patient is benefitting from therapy, and the grade 
4 toxicity is transient, has recovered to ≤ grade 
1, and is unlikely to recur with retreatment.
7.
ADVERSE EVENTS:  LIST AND REPORTING REQUIREMENTS 
Adverse event (AE) monitoring and reporting is a routine part of every clinical trial.  The 
following list of reported and/or potential AEs (Section 7.1) and the characteristics of an 
observed AE (Section 7.2) will determine whether the event requires expedited reporting in 
addition to routine reporting.
7.1
Expected Toxicities
7.1.1
Adverse Events Lists
7.1.1.1
Adverse Event List for Nivolumab
Categorization of AEs Potentially Associated with Nivolumab
In order to characterize AEs of special clinical interest that are potentially associated with the use 
of nivolumab, the Sponsor identified select AEs based on the following 4 guiding principles:

AEs that may differ in type, frequency, or severity from AEs caused by non-
immunotherapies

AEs that may require immunosuppression (e.g., corticosteroids) as part of their 
management

AEs whose early recognition and management may mitigate severe toxicity

AEs for which multiple event terms may be used to describe a single type of AE, thereby 
necessitating the pooling of terms for full characterization
Based on these guiding principles and taking into account the types of AEs already observed 
across studies of nivolumab monotherapy, endocrinopathies, diarrhea/colitis, hepatitis, 
pneumonitis, nephritis, and rash are currently considered to be select AEs. Multiple event terms 
that may describe each of these are grouped into endocrine, GI, hepatic, pulmonary, renal, and 
skin select AE categories, respectively. The list of AEs belonging to select AE categories may 
evolve as more safety information becomes available in the nivolumab program.
Hypersensitivity/infusion reactions were also analyzed along with the select AE categories 
because multiple AE terms may be used to describe these events, and therefore, pooling of terms 
provides a more complete characterization of the events. Hypersensitivity/infusion reactions do 
not, otherwise, meet criteria to be considered select AEs.
Serious Adverse Events Reported from Clinical Trials with Nivolumab Monotherapy

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As of May 2014, the following serious AEs have been reported in clinical studies in which 
nivolumab was given as monotherapy. The frequency of ADRs is defined using the following 
convention: very common (≥ 1/10); common (≥ 1/100 to < 1/10); uncommon (≥ 1/1,000 to < 
1/100); rare (≥ 1/10,000 to < 1/1,000); and very rare (< 1/10,000). There are no very common or 
very rare SAEs associated with nivolumab monotherapy. For further information, including 
SAEs that are rarely associated, please reference the IB.
The following common SAE is associated: pneumonitis
The following uncommon SAEs by system organ class are associated:

Endocrine: Adrenal insufficiency, Hypothyroidism

Gastrointestinal: Abdominal pain, Colitis, Diarrhea, Nausea, Pancreatitis, Vomiting

General and Administrative Site Conditions: Mucosal inflammation, Pyrexia

Hepatobiliary: Abnormal hepatic function

Immune system: Hypersensitivity

Injury, Poisoning and Procedural Complications: Infusion-related reaction

Metabolism and Nutrition: Dehydration, Hyperglycemia

Renal and Urinary: Acute renal failure, Tubulointerstitial nephritis

Respiratory, Thoracic and Mediastinal Disorders: Dyspnea, Hypoxia, Interstitial lung 
disease, Lung infiltration, Respiratory failure
Nonserious Adverse Events Reported from Clinical Trials with Nivolumab Monotherapy
As of May 2014, the following nonserious AEs have been reported in clinical studies in which 
nivolumab was given as monotherapy. The frequency of ADRs is defined using the following 
convention: very common (≥ 1/10); common (≥ 1/100 to < 1/10); uncommon (≥ 1/1,000 to < 
1/100); rare (≥ 1/10,000 to < 1/1,000); and very rare (< 1/10,000).
The following very common nonserious AEs are associated: Fatigue, Nausea, Pruritus
The following common nonserious AEs are associated: Arthralgia, Asthenia, Cough, Decreased 
appetite, Diarrhea, Pyrexia, Rash
A complete list of adverse events observed with nivolumab are detailed in the Investigator’s 
Brochure (IB). 
7.1.1.2
Adverse Event List for Bevacizumab
Bevacizumab is FDA-approved in conjunction with paclitaxel, topotecan, or pegylated liposomal 
doxorubicin for the treatment of platinum-resistant ovarian cancer and together with platinum-
based chemotherapy for the treatment of platinum-sensitive ovarian cancer. Bevacizumab is 
associated with a number of toxicities, including hypertension, headache, epistaxis, hoarseness, 
proteinuria, thromboembolic events (venous and arterial), arthralgia, myalgia, infection, impaired 
healing, bleeding events, gastrointestinal perforation, fistula formation, myelosuppression, and 
allergic or infusion reactions.

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Please refer to the FDA package insert for a comprehensive list of adverse events.
7.1.1.3
Adverse Event List for Rucaparib
The most common treatment-emergent adverse events (TEAEs) were nausea, asthenia/fatigue, 
vomiting, anemia/hemoglobin decreased, alanine aminotransferase (ALT)/aspartate 
aminotransferase (AST) increased, constipation, decreased appetite, and dysgeusia. Commonly 
experienced Grade 3 or higher TEAEs included anemia/hemoglobin decreased, asthenia/fatigue, 
and ALT/AST increased. Results of a more recent integrated safety analysis for rucaparib 
treatment in over 900 patients with ovarian cancer who received 600 mg BID rucaparib in either 
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,ALT/AST increased, decreased appetite, and dysgeusia. The most 
common TEAEs≥ Grade 3 included anemia/decreased hemoglobin, ALT/AST increased, 
neutropenia/decreased absolute neutrophil count (ANC), and asthenia/fatigue.
A complete list of adverse events observed with rucaparib are detailed in the Investigator’s 
Brochure (IB).
7.2
Adverse Event Characteristics

CTCAE term (AE description) and grade:  The descriptions and grading scales found 
in the revised NCI Common Terminology Criteria for Adverse Events (CTCAE) version 
4.0 will be utilized for AE reporting.  All appropriate treatment areas should have access 
to a copy of the CTCAE version 4.0.  A copy of the CTCAE version 4.0 can be 
downloaded from the CTEP web site 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm.

For expedited reporting purposes only:  
-
AEs for the agent(s) that are listed above should be reported only if the adverse event 
varies in nature, intensity or frequency from the expected toxicity information which 
is provided.
-
Other AEs for the protocol that do not require expedited reporting are outlined in 
section 7.3 (Serious Adverse Event).

Attribution of the AE:
-
Definite – The AE is clearly related to the study treatment.
-
Probable – The AE is likely related to the study treatment.
-
Possible – The AE may be related to the study treatment.
-
Unlikely – The AE is doubtfully related to the study treatment.
-
Unrelated – The AE is clearly NOT related to the study treatment.
7.3
Serious Adverse Event (SAE)
A Serious Adverse Event (SAE) is any untoward medical occurrence that at any dose: 

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57

results in death

is life-threatening (defined as an event in which the subject was at risk of death at the time 
of the event; it does not refer to an event which hypothetically might have caused death if 
it were more severe)

requires inpatient hospitalization or causes prolongation of existing hospitalization (see 
NOTE below)

results in persistent or significant disability/incapacity

is a congenital anomaly/birth defect 

is an important medical event (defined as a medical event(s) that may not be immediately 
life-threatening or result in death or hospitalization but, based upon appropriate medical 
and scientific judgment, may jeopardize the subject or may require intervention [e.g., 
medical, surgical] to prevent one of the other serious outcomes listed in the definition 
above.) Examples of such events include, but are not limited to, intensive treatment in an 
emergency room or at home for allergic bronchospasm; blood dyscrasias or convulsions 
that do not result in hospitalization.) 

Potential drug induced liver injury (DILI) is also considered an important medical event. 

Suspected transmission of an infectious agent (e.g., pathogenic or nonpathogenic) via the 
study drug is an SAE. 

Although pregnancy, overdose, and cancer are not always serious by regulatory definition, 
these events must be handled as SAEs.
NOTE: The following hospitalizations are not considered SAEs: 

a visit to the emergency room or other hospital department < 24 hours, that does not result 
in admission (unless considered an important medical or life-threatening event)

elective surgery, planned prior to signing consent

admissions as per protocol for a planned medical/surgical procedure

routine health assessment requiring admission for baseline/trending of health status (e.g., 
routine colonoscopy)

Medical/surgical admission other than to remedy ill health and planned prior to entry into 
the study. Appropriate documentation is required in these cases

Admission encountered for another life circumstance that carries no bearing on health 
status and requires no medical/surgical intervention (e.g., lack of housing, economic 
inadequacy, caregiver respite, family circumstances, administrative reason).
7.4
Expedited Adverse Event Reporting 
7.4.1
Investigators must report to the Overall PI any serious adverse event (SAE) that occur 
during the screening period and within 100 days of the last dose of study treatment on the 
local institutional SAE form. For participants enrolled on study but never treated with 
study drug, SAEs should be collected for 30 days from the date of enrollment. 
7.4.2
DF/HCC Expedited Reporting Guidelines
Investigative sites within DF/HCC will report AEs directly to the DFCI Office for 
Human Research Studies (OHRS) per the DFCI IRB reporting policy. 

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8.1.1
Description
Nivolumab is also referred to as BMS-936558-01 or BMS-936558. Nivolumab is a 
soluble protein consisting of 4 polypeptide chains, which include 2 identical heavy chains 
and 2 identical light chains. The physical and chemical properties of nivolumab are 
provided in Table 8.1.1 below. The geometric mean of terminal T-HALF was 25.6 days 
and the typical clearance was 8.8 mL/h, which are consistent with those of full human 
immunoglobulin antibodies. 
Table 8.1.1: Nivolumab Physical and Chemical Properties
BMS Number
BMS-936558-01
Other Names
Nivolumab, BMS-936558, MDX1106, ONO-4538, anti-
PD-1
Molecular Weight
146,221 daltons
Appearance
Clear to opalescent, colorless to pale yellow liquid, light 
(few) particulates may be present
Solution pH
5.5 to 6.5
8.1.2
Form
Nivolumab Injection, 100 mg/10 mL (10 mg/mL) and Nivolumab Injection, 40 mg/4 mL 
(10 mg/mL)
Nivolumab Injection, 100 mg/10 mL (10 mg/mL) or 40 mg/4 mL (10 mg/mL), is a clear 
to opalescent, colorless to pale yellow liquid, which may contain light (few) particulates. 
The drug product is a sterile, nonpyrogenic, single-use, isotonic aqueous solution 
formulated at 10 mg/mL in sodium citrate, sodium chloride, mannitol, 
diethylenetriaminepentacetic acid (pentetic acid), and polysorbate 80 (Tween™ 80), pH 
6.0 and includes a 0.7-mL overfill to account for vial, needle, and syringe (VNS) holdup. 
It is supplied in 10-cc Type I flint glass vials, stoppered with butyl rubber stoppers and 
sealed with aluminum seals. The only difference between the two drug product 
presentations is the vial fill volume.
PRODUCT INFORMATION TABLE: 
Product Description:(Other names = MDX-1106, ONO-4538, anti-PD-1)
Product 
Description 
and Dosage 
Form
Potency
Primary 
Packaging
(Volume)/ 
Label Type
Secondary 
Packaging
(Qty) 
/Label 
Type
Appearance
Storage 
Conditions
(per label)
Nivolumab 
(BMS-
936558-01)* 
100 
mg/Vial 
(10 
Carton of 5 
or 10 vials
10-cc Type 
1 flint glass 
vials 
Clear to 
opalescent, 
colorless to 
BMS-
936558-01 
Injection 

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*Nivolumab may* be labeled as BMS-936558-01 Solution for Injection.
8.1.3
Storage and Stability
Nivolumab Injection, 100 mg/10 mL (10 mg/mL) and 40 mg/4 mL (10 mg/mL)
Vials of nivolumab injection must be stored at 2˚to 8˚C (36˚to 46˚F) and protected from 
light, freezing, and shaking.
If any temperature excursions are encountered during storage, please report these to BMS 
for assessment via the Temperature Excursion Response Form.
If stored in a glass front refrigerator, vials should be stored in the carton.
Partially used vials should be disposed at the site following procedures for the disposal of 
anticancer drugs. 
After final drug reconciliation, unused nivolumab vials should be disposed at the site 
following procedures for the disposal of anticancer drugs. For further information, please 
either discuss with your BMS CSR&O protocol manager or refer to your site IP 
Destruction policies and procedures.
Diluted Nivolumab Injection in the IV Bag
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°to 8°C, 36°to 46°F) for up to 24 hours, and a maximum of 8 
hours of the total 24 hours can be at room temperature (20˚to 25˚C, 68˚to 77˚F) and room 
light. The maximum 8-hour period under room temperature and room light conditions 
includes the product administration period.
8.1.4
Compatibility
Nivolumab injection will be infused diluted with 0.9% Sodium Chloride Injection, USP 
or 5% Dextrose Injection, USP to protein concentrations as low as 0.35 mg/mL.
Injection 
drug product 
is a sterile, 
non-
pyrogenic, 
single-use, 
isotonic 
aqueous 
solution 
formulated at 
10 mg/mL  
mg/mL).
stoppered 
with butyl 
stoppers and 
sealed with 
aluminum 
seals.
pale yellow 
liquid.  May 
contain 
particles
must be 
stored at 2 to 
8 degrees C 
(36 to 46 
degrees F) 
and 
protected 
from light 
and freezing 

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8.1.5
Handling
Qualified personnel, familiar with procedures that minimize undue exposure to 
themselves and the environment, should undertake the preparation, handling, and safe 
disposal of the chemotherapeutic agent in a self-contained and protective environment. 
As with all injectable drugs, care should be taken when handling and preparing 
nivolumab. Whenever possible, nivolumab should be prepared in a laminar flow hood or 
safety cabinet using standard precautions for the safe handling of intravenous agents 
applying aseptic technique. Recommended safety measures for preparation and handling 
of nivolumab include laboratory coats and gloves.
8.1.6
Availability
Nivolumab is an investigational agent and will be supplied free of charge from Bristol-
Myers Squibb.
8.1.7
Preparation

Visually inspect the drug product solution for particulate matter and discoloration prior to 
administration.  Discard if solution is cloudy, if there is pronounced discoloration 
(solution may have a pale-yellow color), or if there is foreign particulate matter other 
than a few translucent-to-white, amorphous particles.
Note: Mix by gently inverting several times.  Do not shake.

Aseptically withdraw the required volume of nivolumab solution into a syringe, and 
dispense into an IV bag.  If multiple vials are needed for a subject, it is important to use a 
separate sterile syringe and needle for each vial to prevent problems such as dulling of 
needle tip, stopper coring, repeated friction of plunger against syringe barrel wall. Do not 
enter into each vial more than once.  Do not administer study drug as an IV push or bolus 
injection

Add the appropriate volume of 0.9% Sodium Chloride Injection solution or 5% Dextrose 
Injection solution. It is acceptable to add nivolumab solution from the vials into an 
appropriate pre-filled bag of diluent.
Note: Nivolumab infusion concentration must be at or above the minimum allowable 
concentration of 0.35 mg/mL.
Note: Nivolumab infusion should not exceed a total infusion volume of 120 mL. 
Note: It is not recommended that so-called “channel” or tube systems are used to transport 
prepared infusions of nivolumab.

Attach the IV bag containing the nivolumab solution to the infusion set and filter.

At the end of the infusion period, flush the line with a sufficient quantity of approved 
diluents.

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Please refer to section 3.2.3 of the current Investigator Brochure. Due to parameters 
surrounding the use time of nivolumab, the time of preparation should be noted in the 
Pharmacy Source documents [accountability logs] or in study files as required for 
investigator sponsored research [FDA and GCP].
8.1.8
Administration
The administration of BMS-936558-01 injection prepared for dosing nivolumab infusion 
must be completed within 24 hours of preparation. If not used immediately, the infusion 
solution may be stored up to 20 hours in a refrigerator at under refrigeration conditions 
(2° to 8°C (, 36° to 46°F) and used within 4 for up to 24 hours, and a maximum of 8 
hours of the total 24 hours can be at room temperature (20° to 25°C, 68° to 77°F) and 
under room light. The maximum 4-hour period under room temperature and room light 
conditions for diluted solutions of BMS-936558-01 injection in the IV bag should be 
inclusive of the includes the product administration period.
Nivolumab will be given every two weeks at a dose of 240 mg to be administered as a 30 
minute IV infusion.
Subjects may be dosed no less than 12 days from the previous dose of drug. There are no 
premedications recommended for nivolumab on the first cycle. There will be no dose 
modifications allowed.
Subjects should be carefully monitored for infusion reactions during nivolumab 
administration. If an acute infusion reaction is noted, subjects should be managed 
according to Protocol Section 6.7.
Doses of nivolumab may be interrupted, delayed, or discontinued depending on how well 
the subject tolerates the treatment.
Nivolumab Injection, 100 mg/10 mL (10 mg/mL) and 40 mg/4 mL (10 mg/mL)
Nivolumab injection is to be administered as an IV infusion through a 0.2-micron to 1.2-
micron pore size, low-protein binding polyethersulfone membrane in-line filter at the 
protocol-specified doses and infusion time. It is not to be administered as an IV push or 
bolus injection. Nivolumab injection will be infused diluted with 0.9% Sodium Chloride 
Injection, USP or 5% Dextrose Injection, USP to protein concentrations as low as 0.35 
mg/mL. Care must be taken to assure sterility of the prepared solution as the product does 
not contain any antimicrobial preservative or bacteriostatic agent. No incompatibilities 
between nivolumab and polyvinyl chloride (PVC), non-PVC/non-DEHP (di(2-
ethylhexyl) phthalate) IV components, or glass bottles have been observed.
8.1.9
Ordering
It is possible that sites may have more than one clinical study on the same drug ongoing 
at the same time. It is imperative that only drug product designated for this protocol be 
used for this study

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If concerns regarding the quality or appearance of the investigational product arise, do 
not dispense the investigational product, and contact BMS immediately. If commercial 
investigational product is used, it should be stored in accordance with the appropriate 
local labeling
Initial Orders 

Following submission and approval of the required regulatory documents, a supply of 
nivolumab may be ordered from by completing a Drug Request Form provided by BMS 
for this specific trial. 

Nivolumab will be supplied in 100 mg vials.

The initial order should be limited to 20 vials. Allow 5 business days for shipment of 
drug from BMS receipt of the Drug Request Form. Drug is protocol specific, but not 
patient specific. All drug product will be shipped by courier in a temperature-controlled 
container. It is possible that sites may have more than one nivolumab clinical study 
ongoing at the same time. It is imperative that only drug product designated for this 
protocol number be used for this study.

Pharmacy supplies not provided by BMS:  Empty IV bags/containers, approved 
diluents,  In-line filters and infusion tubing
Re-Supply

Drug re-supply request form should be submitted electronically 2 weeks before the 
expected delivery date.  Deliveries will be made Tuesday through Friday.

When assessing need for resupply, institutions should keep in mind the number of vials 
used per treatment dose, and that shipments may take 14 business days from receipt of 
request. Drug is not patient-specific. Be sure to check with your pharmacy regarding 
existing investigational stock to assure optimal use of drug on hand.
Drug Excursions

Drug  excursions should be reported immediately to BMS on the form provided with 
the study-specific drug order form
8.1.10 Accountability
The investigator, or a responsible party designated by the investigator, should maintain a 
careful record of the inventory and disposition of the agent using the NCI Drug 
Accountability Record Form (DARF) or another comparable drug accountability form.  
(See the NCI Investigator’s Handbook for Procedures for Drug Accountability and 
Storage.)
8.1.11 Destruction and Return
Expired and unused supplies of nivolumab will be destroyed according to institutional 
policies. Destruction will be documented in the Drug Accountability Record Form.

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8.2
Bevacizumab
8.2.1
Description
Bevacizumab (Avastin ® or biosimilar product) is a recombinant, humanized, 
monoclonal antibody with high affinity for binding to vascular endothelial growth factor 
receptor (VEGF). Bevacizumab is an IgG1 antibody that contains human framework 
regions and the complementarity determining regions of a murine antibody that binds to 
VEGF.
8.2.2
Form
Bevacizumab is a clear to slightly opalescent, colorless to pale brown, sterile, pH 6.2 
solution for intravenous infusion. It is supplied in 100 mg and 400 mg preservative-free, 
single-use vials to deliver 4 mL or 16 mL of Avastin (25 mg/mL).
8.2.3
Storage and Stability
Bevacizumab vials [100 mg (NDC 50242-060-01) and 400 mg (NDC 50242-061-01)] are 
stable at 2−8°C (36−46°F). Vials should be protected from light and should not be frozen 
or shaken. Diluted bevacizumab solutions may be stored at 2−8°C (36−46°F) for up to 8 
hours. They should be stored in the original carton until time of use.
8.2.4
Compatibility
The 100 mg product is formulated in 240 mg α,α-trehalose dihydrate, 23.2 mg sodium 
phosphate (monobasic, monohydrate), 4.8 mg sodium phosphate (dibasic, anhydrous), 
1.6 mg polysorbate 20, and water for injection, USP. The 400 mg product is formulated 
in 960 mg α,α-trehalose dihydrate, 92.8 mg sodium phosphate (monobasic, 
monohydrate), 19.2 mg sodium phosphate (dibasic, anhydrous), 6.4 mg polysorbate 20, 
and water for injection, USP [24]. No incompatibilities between bevacizumab and 
polyvinylchloride or polyolefin bags have been observed.
8.2.5
Handling
Qualified personnel, familiar with procedures that minimize undue exposure to 
themselves and the environment, should undertake the preparation, handling, and safe 
disposal of the chemotherapeutic agent in a self-contained and protective environment.
8.2.6
Availability and Ordering
Bevacizumab is a commercially available agent.
8.2.7
Preparation and Administration
Bevacizumab may be prepared per institutional guidelines. It should be given 
intravenously over 30 minutes, though infusion duration may vary per institutional 

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guidelines.
8.2.8
Accountability
The investigator, or a responsible party designated by the investigator, must maintain a 
careful record of the inventory and disposition of the agent (investigational or free of 
charge) using the NCI Drug Accountability Record or another comparable drug 
accountability form. (See the CTEP website at http://ctep.cancer.gov/protocol 
Development for the “Policy and Guidelines for Accountability and Storage of 
Investigational Agents” or to obtain a copy of the drug accountability form.)
8.2.9
Destruction and Return
At the end of the study, unused supplies of bevacizumab should be returned according to 
institutional policies. Destruction will be documented in the Drug Accountability Record 
Form.
8.3
Rucaparib
8.3.1
Description
Rucaparib is a potent small molecule inhibitor of poly-adenosine diphosphate (ADP) 
ribose polymerase (PARP) enzymes, including PARP-1, PARP-2, and PARP-3.  
8.3.2
Form
Rucaparib is supplied as, , 200mg, 250mg, and 300mg . film coated tablets:  The physical 
appearances of the tablets are unique in order to ensure proper identification....: 200 mg 
(blue, round, debossed with C2), 250 mg (white, rounded diamond shape, debossed with 
C25), 300 mg (yellow, oval, debossed with C3)
8.3.3
Storage and Stability
Rucaparib tablets are provided in HDPE bottles and should be stored in the provided 
containers between 15°C and 30°C.
8.3.4
Handling
Qualified personnel, familiar with procedures that minimize undue exposure to 
themselves and the environment, should undertake the preparation, handling, and safe 
disposal of the chemotherapeutic agent in a self-contained and protective environment.
8.3.5
Availability and Ordering
Rucaparib is an investigational agent and was supplied free of charge by Clovis for use in 
this clinical trial prior to its acquisition by Pharma& as of 01 May 2023.

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8.3.6
Accountability
The investigator, or a responsible party designated by the investigator, must maintain a 
careful record of the inventory and disposition of the agent (investigational or free of 
charge) using the NCI Drug Accountability Record or another comparable drug 
accountability form. (See the CTEP website at http://ctep.cancer.gov/protocol 
Development for the “Policy and Guidelines for Accountability and Storage of 
Investigational Agents” or to obtain a copy of the drug accountability form.)
8.3.7
Destruction and Return
Expired and unused supplies of rucaparib will be destroyed according to institutional 
policies. Destruction will be documented in the Drug Accountability Record Form.
8.3.8
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 in patients on rucaparib taking concomitant medicines 
that are substrates of CYP1A2, CYP2C9, and/or CYP3A with narrow therapeutic 
windows (see IB, Appendix B). 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. 
Selection of an alternative concomitant medication is recommended. 
Anticoagulants
Rucaparib is a weak inhibitor of CYP2C9 in vivo. Caution should be exercised in patients 
receiving rucaparib and concomitant warfarin (Coumadin). Patients taking warfarin 
should have INR monitored regularly per standard clinical practice.
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. 

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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 (eg, rosuvastatin).
9.
BIOMARKER, CORRELATIVE, AND SPECIAL STUDIES
9.1
Biomarker Studies
A variety of factors that could potentially predict clinical response to nivolumab plus 
bevacizumab will be investigated in peripheral blood and in tumor specimens taken from all 
subjects prior to treatment and as outlined in Biomarker Sampling Schedule table in Section 10. 
Data from these investigations will be evaluated for associations with response, survival (OS, 
PFS) and/or safety (adverse event) data. All samples collected may also be used for future 
exploratory analyses (unless restricted by local requirements) to assess biomarkers associated 
with ovarian cancer or immunotherapy plus antiangiogenic treatment.
9.1.1
Tumor Tissue Specimens
9.1.1.1
Pre-treatment biopsy
Tumor biopsy specimens will be obtained from consenting subjects prior to treatment with 
nivolumab plus bevacizumab. All participants who do not have an archival sample that was 
obtained within 20 months of study entry must undergo pre-treatment biopsy, as the expression 
of PD-L1 degrades over time and could not be reliably assessed in samples older than 20 months.  
Pre-treatment biopsy is encouraged but is not mandatory for participants who have available 
archival tissue that was obtained within 20 months of study entry.  Biopsies from bone lesions 
are not suitable for tumor specimens since the decalcification process is not compatible with 
several planned biomarker analyses.
The investigator, in consultation with the radiology staff, must determine the degree of risk 
associated with the procedure and find it acceptable. Biopsies may be done with local anesthesia 
or conscious sedation. Institutional guidelines for the safe performance of biopsies should be 
followed. Excisional biopsies may be performed to obtain tumor biopsy samples. Invasive 
procedures that require general anesthesia should not be performed to obtain a biopsy specimen. 
However, if a surgical procedure is performed for a clinical indication, excess tumor tissue may 
be used for research purposes with the consent of the subject.
A minimum of 2 and up to 5 cores of a 16 to 18 gauge size should be collected under 
institutional guidelines for biopsy procedures.  Biopsies should be immediately placed in 10% 
formalin and subsequently embedded in paraffin under standard procedures.
These tumor samples may also be assessed for the expression of other immune or ovarian 
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10. STUDY CALENDAR AND BIOMARKER SAMPLING SCHEDULE
Baseline evaluations are to be conducted within 2 weeks prior to start of protocol therapy.  
Scans, Echocardiograms, and x-rays must be done <4 weeks prior to the start of therapy.  In the 
event that the participant’s condition is deteriorating, laboratory evaluations should be repeated 
within 48 hours prior to initiation of the next cycle of therapy.
Assessments must be performed prior to administration of any study agent. Study assessments 
and agents should be administered within + 3 days of the protocol-specified date, unless 
otherwise noted.
NB: One cycle is 2 weeks in length
STUDY CALENDAR
Procedures
Screen
Cycle 1
Cycle 2
Cycle 3
Cycle 4 +
Nivolumab 
Discontinuationl
Off-Tx
Follow-
Up
Day 1
Day 8
Day 1
Day 8
Day 1
Day 1
Treatment 
Nivolumab
X
X
X
X
Treatment 
Bevacizumab
X
X
X
X
Xl
Treatment 
Rucaparibk
Oral dosing twice daily
Xl
Demographics
X
Medical history
X
Concurrent meds
X
X
X
X
X
X
X
Physical exam
X
X
X
X
X
X
X
Vital signs a
X
X
X
X
X
X
X
Height
X
Weight
X
X
X
X
X
X
X
Performance Status
X
X
X
X
X
X
X
Blood tests b,j
X
X
X
X
X
X
X
X
X
Coagulation 
parameters (INR, 
aPTT)
X
TSH (with Free T4)
X
X
X c
X
X
EKG
X
U/A or urine 
protein:creatine 
ratioo
X
X
X
X
X
X
X
Hepatitis B and C 
testing d
X
Echocardiogrami
X
Adverse event 
evaluation 
X
X
X
X
X
X
X e
Tumor restaging
X
Tumor measurements are repeated every 4 cycles (+/- 1 
week), e.g, C5D1, C9D1, C13D1, etc.n
Xm
Oxygen saturation  f
X
X
X
X
X
Pregnancy Test g
X
X g
X g
X g
CA-125
X
CA-125 is performed every 4 weeks (2 cycles) (+/- 1 week)
X
X
Survival 
Assessment
X h
a:     Temperature, blood pressure, pulse, respiratory rate, oxygen saturation

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b:
CBC with differential, sodium, potassium, chloride, bicarbonate, BUN, creatinine, glucose, calcium, magnesium, LDH, SGPT [ALT], SGOT 
[AST], total bilirubin, alkaline phosphatase, amylase, lipase. Patients in cohort 2 and cohort should have a fasting lipid panel performed every 
6 weeks (every 3 cycles); if patients have permanently discontinued rucaparib, the fasting lipid panel may be omitted.
c:     Thyroid function testing should be done every 6 weeks (every 3 cycles).
d:     Hepatitis B and C testing (HBV sAg and HCV Ab or HCV RNA) should be done within 28 days prior to first dose
e:     Follow for 100 days following last receipt of study treatment.
f:      Oxygen saturation by pulse oximetry at rest (also monitor amount of supplemental oxygen if applicable) should be assessed at each on-study 
visit prior to dosing
g:
Serum or urine pregnancy testing is required for women of childbearing potential within 24 hrs of study enrollment or randomization. Serum 
or urine pregnancy test should be repeated every 3 cycles. After discontinuation from nivolumab these should be repeated at approximately 
30days and approximately 70 days
h:     Every 3 months until death
i:      Echocardiogram should be done at baseline for patients who have has prior treatment with anthracyclines.
j:      Patients enrolled to cohort 2 and cohort 3 should have weekly CBC with differential through the first two cycles (e.g., on Cycle 1 Day 1 and 
Day 8 and on Cycle 2 Day 1 and Day 8).
k:    For patients in cohort 2 and cohort 3 only
l:     Patients will be treated on nivolumab for up to 2 years (treatment may continue beyond 2 years per investigator and patient discretion), after 2 
years patients have the option to continue on bevacizumab alone or discontinue both drugs should nivolumab be stopped. Patients who 
discontinue nivolumab and continue on bevacizumab alone (Cohort 1) or bevacizumab/rucaparib (Cohort 2 and Cohort 3) will follow the main 
study calendar. Patients discontinuing all drugs will need to be evaluated every 12 weeks (+/- 1 week), as defined in the “Nivolumab 
Discontinuation” column, in order to be re-challenged. If the patient subsequently progresses re-challenge is allowed after discussion with the 
Overall PI and meeting the criteria outlined in section 5.2.3.
m:   Patients who discontinue all drugs will undergo tumor restaging every 8-12 weeks, this can be done more frequently at the discretion of the 
treating physician. 
n:     Patients continuing study treatment for a minimum of 1 year may have the interval of repeated tumor measurements expanded to every 6 
cycles (e.g. every 12 weeks) +/- 1 week. 
o:     Urine studies may be omitted if patients have permanently discontinued bevacizumab if clinically appropriate per investigator discretion
BIOMARKER SAMPLING SCHEDULE
Samples a
Screen
Cycle 1
Day 1
Cycle 2
Day 1
Cycle 3
Day 1
Off 
Treatment 
Serum biomarkers
X
X
X
X
Tumor biopsy or archival 
tissue sample b
X
Whole blood
X
a     All biomarker samples may be obtained +/- 3 days from the indicated timepoint.  Cycle 1 Day 1, Cycle 2 
Day 1, and Cycle 3 Day 1 biomarkers must be obtained prior to receiving nivolumab/bevacizumab study 
treatment.
b     Pre-treatment biopsy must be obtained within 2 weeks prior to start of protocol therapy on all participants 
who do not have an archival sample obtained within the last 20 months.  Biopsy is optional but strongly 
encouraged in participants where an archival sample obtained within the prior 20 months is available.
All serum biomarkers and whole blood samples will need to be labelled with the following 
information:

Study number

Subject number

Time point

Sample Type
For all tumor biopsy and archival tissue samples please collect the following information:

Copy of de-identified pathology report 

Original block ID 

Collection method 

Date of biopsy 

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
Site/organ of biopsy 

Site of collection (primary or metastatic)
11. MEASUREMENT OF EFFECT
11.1
Antitumor Effect – Solid Tumors
For the purposes of this study, participants should be re-evaluated for response every 4 cycles 
(approximately 8 weeks).  In addition to a baseline scan, confirmatory scans should also be 
obtained (not less than 4) weeks following initial documentation of objective response.  The next 
planned scans may be used as the confirmatory scans.
Response and progression will be evaluated in this study using the new international criteria 
proposed by the Response Evaluation Criteria in Solid Tumors (RECIST) guideline (version 1.1) 
[Eur J Ca 45:228-247, 2009] and as per immune-related RECIST criteria (irRC).  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 criteria.
11.1.1 Definitions
Evaluable for Target Disease response.  Only those participants who have measurable 
disease present at baseline, have received at least one cycle of therapy, and have had their 
disease re-evaluated will be considered evaluable for target disease response.  These 
participants will have their response classified according to the definitions stated below.  
(Note:  Participants who exhibit objective disease progression prior to the end of cycle 1 
will also be considered evaluable.)
Evaluable Non-Target Disease Response.  Participants 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. 
11.1.2 Disease Parameters
Measurable disease.  Measurable lesions are defined as those that can be accurately 
measured in at least one dimension (longest diameter  to be recorded) as ≥ 20 mm by 
chest x-ray or ≥10 mm with CT scan, MRI, or calipers by clinical exam.  All tumor 
measurements must be recorded in millimeters (or decimal fractions of centimeters).
Note: Tumor lesions that are situated in a previously irradiated area may be considered 
measurable if progression has been observed in the lesions following completion of the 
radiation course. 
Malignant lymph nodes.  To be considered pathologically enlarged and measurable, a 
lymph node must be ≥15 mm in short axis when assessed by CT scan (CT scan slice 

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thickness recommended to be no greater than 5 mm).  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 or pathological lymph nodes with ≥10 to <15 mm short axis), 
are considered non-measurable disease.  Bone lesions, leptomeningeal disease, ascites, 
pleural/pericardial effusions, lymphangitis cutis/pulmonitis, inflammatory breast disease, 
abdominal masses (not followed by CT or MRI), and cystic lesions are all considered 
non-measurable.
Note: Cystic lesions that meet the criteria for radiographically defined simple cysts 
should not be considered as malignant lesions (neither measurable nor non-measurable) 
since they are, by definition, simple cysts.
‘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 participant, these are preferred for selection as 
target lesions.
Target lesions.  All measurable lesions up to a maximum of 2 lesions per organ and 5 
lesions in total, representative of all involved organs, should be identified as target 
lesions and recorded and measured at baseline.  Target lesions should be selected on the 
basis of their size (lesions with the longest diameter), be representative of all involved 
organs, but in addition should be those that lend themselves to reproducible repeated 
measurements. It may be the case that, on occasion, the largest lesion does not lend itself 
to reproducible measurement in which circumstance the next largest lesion which can be 
measured reproducibly should be selected. 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. Measurements of these lesions are not required, but 
the presence, absence, or in rare cases unequivocal progression of each should be noted 
throughout follow up. 
11.1.3 Methods for Evaluation of Disease
All measurements should be taken and recorded in metric notation using a ruler, calipers, 
or a digital measurement tool.  All baseline evaluations should be performed as closely as 
possible to the beginning of treatment and never more than 4 weeks before the beginning 
of the treatment.

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The same method of assessment and the same technique should be used to characterize 
each identified and reported lesion at baseline and during follow-up. Imaging-based 
evaluation is preferred to evaluation by clinical examination unless the lesion(s) being 
followed cannot be imaged but are assessable by clinical exam. 
Clinical lesions. Clinical lesions will only be considered measurable when they are 
superficial (e.g., skin nodules and palpable lymph nodes) and ≥10 mm in diameter as 
assessed using calipers (e.g., skin nodules).  In the case of skin lesions, documentation by 
color photography, including a ruler to estimate the size of the lesion, is recommended. 
Chest x-ray.  Lesions on chest x-ray are acceptable as measurable lesions when they are 
clearly defined and surrounded by aerated lung; however, CT is preferable. 
Conventional CT and MRI. This guideline has defined measurability of lesions on CT 
scan based on the assumption that CT thickness is 5mm or less. If CT scans have slice 
thickness greater than 5 mm, the minimum size of 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.
PET-CT. At present, the low dose or attenuation correction CT portion of a combined 
PET-CT is not always of optimal diagnostic CT quality for use with RECIST 
measurements.  However, if the site can document that the CT performed as part of a 
PET-CT is of identical diagnostic quality to a diagnostic CT (with IV and oral contrast), 
then the CT portion of the PET-CT can be used for RECIST measurements and can be 
used interchangeably with conventional CT in accurately measuring cancer lesions over 
time.  Note, however, that the PET portion of the CT introduces additional data which 
may bias an investigator if it is not routinely or serially performed.  FDG-PET assessment 
alone should not be used to document response or progression.
Ultrasound. Ultrasound is not useful in assessment of lesion size and should not be used 
as a method of measurement. Ultrasound examinations cannot be reproduced in their 
entirety for independent review at a later data and, because they are operator dependent, it 
cannot be guaranteed that the same technique and measurements will be taken from one 
assessment to the next. If new lesions are identified by ultrasound in the course of the 

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study, confirmation by CT or MRI is advised. If there is concern about radiation exposure 
from CT, MRI may be used instead of CT in selected instances. 
Endoscopy, Laparoscopy. The utilization of these techniques for objective tumor 
evaluation is not advised. However, such techniques may be useful to confirm complete 
pathological response when biopsies are obtained or to determine relapse in trials where 
recurrence following complete response (CR) or surgical resection is an endpoint.
Tumor markers. Tumor markers alone cannot be used to assess response. If markers are 
initially above the upper normal limit, they must normalize for a participant to be 
considered in complete clinical response.  Specific guidelines for both CA-125 response 
(in recurrent ovarian cancer) and PSA response (in recurrent prostate cancer) have been 
published [JNCI 96:487-488, 2004; J Clin Oncol 17, 3461-3467, 1999; J Clin Oncol 
26:1148-1159, 2008].  In addition, the Gynecologic Cancer Intergroup has developed 
CA-125 progression criteria which are to be integrated with objective tumor assessment 
for use in first-line trials in ovarian cancer [JNCI 92:1534-1535, 2000].
Cytology, Histology. These techniques can be used to differentiate between partial 
responses (PR) and complete responses (CR) in rare cases (e.g., residual lesions in tumor 
types, such as germ cell tumors, where known residual benign tumors can remain).
The cytological confirmation of the neoplastic origin of any effusion that appears or 
worsens during treatment when the measurable tumor has met criteria for response or 
stable disease is mandatory to differentiate between response or stable disease (an 
effusion may be a side effect of the treatment) and progressive disease.
11.1.4 Response Criteria
11.1.4.1
Evaluation of Target Lesions
Complete Response (CR):  Disappearance of all target lesions.  Any pathological 
lymph nodes (whether target or non-target) must have reduction in short axis to <10 
mm.
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.  (Note:  
the appearance of one or more new lesions is also considered progressions).
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.

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11.1.4.2
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 
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 Principal 
Investigator).
11.1.4.3
Evaluation of New Lesions
The finding of a new lesion should be unequivocal (i.e. not due to difference in 
scanning technique, imaging modality, or findings thought to represent something 
other than tumor (for example, some ‘new’ bone lesions may be simply healing or 
flare of pre-existing lesions). However, a lesion identified on a follow-up scan in an 
anatomical location that was not scanned at baseline is considered new and will 
indicate PD. If a new lesion is equivocal (because of small size etc.), follow-up 
evaluation will clarify if it truly represents new disease and if PD is confirmed, 
progression should be declared using the date of the initial scan on which the lesion 
was discovered.
11.1.4.4
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.
For Participants with Measurable Disease (i.e., Target Disease)
Target 
Lesions
Non-Target 
Lesions
New 
Lesions
Overall 
Response
Best Overall Response when 
Confirmation is Required*

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CR
CR
No
CR
>4 wks Confirmation**
CR
Non-CR/Non-
PD
No
PR
CR
Not evaluated
No
PR
PR
Non-CR/Non-
PD/not 
evaluated
No
PR
>4 wks Confirmation**
SD
Non-CR/Non-
PD/not 
evaluated
No
SD
Documented at least once >4 
wks from baseline**
PD
Any
Yes or No
PD
Any
PD***
Yes or No
PD
Any
Any
Yes
PD
no prior SD, PR or CR

See RECIST 1.1 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:  Participants 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.
11.1.5 Duration of Response
Duration of overall response:  The duration of overall response is measured from the time 
measurement criteria are met for CR or PR (whichever is first recorded) until the first 
date that recurrent or progressive disease is objectively documented (taking as reference 
for progressive disease the smallest measurements recorded since the treatment started, or 
death due to any cause. Participants without events reported are censored at the last 
disease evaluation).
Duration of overall complete response: The duration of overall CR is measured from the 
time measurement criteria are first met for CR until the first date that progressive disease 
is objectively documented, or death due to any cause. Participants without events 
reported are censored at the last disease evaluation.
Duration of stable disease:  Stable disease is measured from the start of the treatment 
until the criteria for progression are met, taking as reference the smallest measurements 
recorded since the treatment started, including the baseline measurements. 
11.1.6 Progression-Free Survival
Overall Survival: Overall Survival (OS) is defined as the time from randomization (or 
registration) to death due to any cause, or censored at date last known alive.

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Progression-Free Survival: Progression-Free Survival (PFS) is defined as the time from 
randomization (or registration) to the earlier of progression or death due to any cause. 
Participants alive without disease progression are censored at date of last disease 
evaluation.
Time to Progression: Time to Progression (TTP) is defined as the time from 
randomization (or registration) to progression, or censored at date of last disease 
evaluation for those without progression reported.
11.1.7 Immune related Response Criteria (irRC)
Immune related response criteria using unidimensional measurements may be used to 
describe tumor shrinkage (Nishino et al., 2014).  This methodology is the same as 
described above for RECIST except:

New lesions do not automatically denote disease progression

The measurement of longest diameter of new measurable lesions are included in the 
sum of the measurements of the original target lesions.
The same method of assessment and the same technique should be used to characterize 
each identified and reported target lesion(s) at baseline and throughout the trial. 
irRECIST criteria are defined as follows: 

Overall immune-related complete response (irCR): Complete disappearance of all 
lesions (whether measurable or not) and no new lesions. All measurable lymph nodes 
also must have a reduction in short axis to <10 mm. 

Overall immune-related partial response (irPR): Sum of the diameters (longest for 
non-nodal lesions, shortest for nodal lesions) of target and new measurable lesions 
decreases >= 30%.

Overall immune-related stable disease (irSD): Sum of the diameters (longest for non-
nodal lesions, shortest for nodal lesions) of target and new measurable lesions neither 
irCR, irPR, (compared to baseline) or immune-related progressive disease (irPD, 
compared to nadir). 

Overall immune-related progressive disease (irPD): Sum of the diameters(longest for 
non-nodal lesions, shortest for nodal lesions)of target and new measurable lesions 
increases >= 20% (compared to nadir), confirmed by a repeat, consecutive 
observation at least 4weeks from the date first documented. 
New measurable lesions: Incorporated into tumor burden (ie, added to the target lesion 
measurements). A lymph node has to be >= 15 mm in short axis to be a measurable new 
lesion and its short axis measurement is included in the sum. Up to 2 new lesions per 
organ and up to 5 new lesions in total can be added to the measurements. 
New non-measurable lesions: Do not define progression but preclude irCR. 
Overall responses derived from changes in index, non-index, and new lesions are outlines 
in the following table.

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Overall Response Derived from Changes in Index, Non-index and New Lesions
Best immune related responses are classified as immune related CR (irCR – 
disappearance of all lesions) or immune related PR (irPR (≥30% reduction from 
baseline).
Immune-related progression-free survival (irPFS) is defined as time from registration (or 
randomization) to the earlier of immune-related progression of disease (irPD) or death 
due to any cause. Participants alive without immune-related disease progression are 
censored at date of last disease evaluation.
11.1.8 Response Review
All films will be reviewed and response evaluated by the DF/HCC Tumor Imaging 
Metrics Core (TIMC). 
12. DATA REPORTING / REGULATORY REQUIREMENTS
Adverse event lists, guidelines, and instructions for AE reporting can be found in Section 7.0 
(Adverse Events: List and Reporting Requirements).
12.1
Data Reporting
12.1.1 Method

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The Office of Data Quality (ODQ) will collect, manage, and perform quality checks on 
the data for this study.
12.1.2 Responsibility for Data Submission
Investigative sites within DF/HCC or DF/PCC are responsible for submitting data and/or 
data forms to the Office of Data Quality (ODQ) in accordance with DF/HCC policies.
12.2
Data Safety Monitoring
The DF/HCC Data and Safety Monitoring Committee (DSMC) will review and monitor toxicity 
and accrual data from this study. The committee is composed of clinical specialists with 
experience in oncology and who have no direct relationship with the study. Information that 
raises any questions about participant safety will be addressed with the Overall PI and study 
team.
The DSMC will review each protocol up to four times a year or more often if required to review 
toxicity and accrual data. Information to be provided to the committee may include: up-to-date 
participant accrual; current dose level information; DLT information; all grade 2 or higher 
unexpected adverse events that have been reported; summary of all deaths occurring with 30 
days of intervention for Phase I or II protocols; for gene therapy protocols, summary of all deaths 
while being treated and during active follow-up; any response information; audit results, and a 
summary provided by the study team. Other information (e.g. scans, laboratory values) will be 
provided upon request. 
12.3
Monitoring
Involvement in this study as a participating investigator implies acceptance of potential audits or 
inspections, including source data verification, by representatives designated by the DF/HCC 
Overall Principal Investigator (or Protocol Chair) or DF/HCC. The purpose of these audits or 
inspections is to examine study-related activities and documents to determine whether these 
activities were conducted and data were recorded, analyzed, and accurately reported in 
accordance with the protocol, institutional policy, Good Clinical Practice (GCP), and any 
applicable regulatory requirements. All data will be monitored for timeliness of submission, 
completeness, and adherence to protocol requirements. Monitoring will begin at the time of 
participant registration and will continue during protocol performance and completion.
12.4
Multicenter Guidelines
N/A
12.5
Collaborative Agreements Language
N/A
13. STATISTICAL CONSIDERATIONS

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13.1
Study Design/Endpoints
The first two cohorts of this study are phase II designs with two sequentially enrolled cohorts, 
each including a safety assessment lead-in, in which the dose limiting toxicities (DLTs) of the 
study agents will be assessed over a 28-day period (two treatment cycles) in the first six 
evaluable patients enrolled. A safety review will occur after these six patients have completed 
two treatment cycles. Further accrual will be held until the regimen is deemed safe.
Within the safety lead-in, patients who do not have a DLT and who do not complete cycle 1 will 
be replaced. All patients that received any treatment will be considered evaluable for a DLT, 
unless they withdraw from the trial for reasons other than toxicity. If one or fewer patient out of 
the first six patients experience DLTs within the first two treatment cycles then the regimen will 
be deemed safe for administration in the phase II study. In cohort 1, if two or more patients out 
of the first six patients experience DLTs then the combination of nivolumab and bevacizumab 
will be declared unsafe and the study will be terminated.  
In cohort 2, if two or more patients out of the first six patient experience DLTs while receiving 
the combination of nivolumab, bevacizumab, and rucaparib, a second safety lead-in of six 
patients will be performed with the combination using the next lower dose level of rucaparib.  If 
one or fewer patients out of the six patients in the second safety lead-in experience DLTs within 
the first two treatment cycles, then the combination of nivolumab, bevacizumab, and rucaparib 
will be deemed safe for administration at this dose level in the phase II study.  If two or more 
patients in the second safety lead-in in cohort 2 experience DLTs, then the combination of 
nivolumab, bevacizumab, and rucaparib will be declared unsafe and no further enrollment will 
occur for this cohort.
True underlying DLT rate
10%
20%
30%
40%
50%
60%
70%
80%
90%
Probability of declaring MTD
89%
66%
42%
23%
11%
4%
1%
0.2%
<0.01%
A DLT is defined as any of the following occurring during the first 28 days of treatment, 
assessed in accordance with the current version of NCI Common Terminology Criteria 
(CTCAE):
Non-Hematologic Toxicity
Any Grade 3 or 4 treatment-related event, excluding the following toxicities: 

Grade 3 fatigue, recovering within 7 days

Grade 3 hypertension controlled with anti-hypertensive therapy

Grade 3 electrolyte disturbances (e.g., hypophosphatemia, hyponatremia, 
hypokalemia) that are asymptomatic and correctable with electrolyte repletion.

Grade 3 or 4 amylase or lipase elevation that is not associated with any signs or 
symptoms of pancreatitis

Grade 3 rash that resolves to grade 2 or grade 1 within < 5 days.

For patients in cohort 2 or cohort 3:

Asymptomatic grade 3 ALT/AST elevation that resolves spontaneously to 
grade 2 or better and does not recur after resumption of triplet combination 

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treatment

Asymptomatic grade 3 elevation in cholesterol
Hematologic Toxicity
a) Grade 4 neutropenia of ≥ 7 days’ duration
b) Grade 4 neutropenia of any duration with fever or documented infection
c) All other Grade 4 hematologic toxicities
In Cohort 3, we will implement sequential boundaries to monitor for DLTs. The accrual to 
Cohort 3 will be halted if excessive numbers of DLTs are seen (see table below). This is a 
Pocock-type stopping boundary that yields the probability of crossing the boundary at most 
17.8% when the rate of DLTs is equal to the acceptable rate 20% and greater than 45.6% when 
DLT rate is 30% or higher.
Number of patients
1
2
3-6
7-9
10-13
14-15
Halt enrollment if these number of 
patients or more experience a DLT
-
2
3
4
5
6
The primary endpoint for the phase II part of the first two cohorts is objective response (CR + 
PR) using standard RECIST 1.1 criteria.
A key secondary endpoint is modified objective response that allows immune related objective 
response subsequent to initial PD per RECIST criteria. Subjects with initial PD per RECIST who 
continue treatment in their initially assigned treatment arm beyond progression (Section 5.8) and 
subsequently reach confirmed immune related CR or PR (relative to initial tumor assessment and 
evaluated by including the measurement of longest diameter of any new measurable lesions in 
the sum of the measurements of the original target lesions, Section 10.1.7) will be considered as 
having an objective response for the purposes of meeting criteria for moving from Stage 1 to 
Stage 2. Although not standard objective response per RECIST, these immune related response 
criteria using unidimensional measurements account for the unusual immune related tumor 
response patterns reported with various immunotherapies, including nivolumab.
The response rate for bevacizumab monotherapy in relapsed ovarian cancer is approximately 
15%. In order to detect a doubling from this comparison to a target response rate to 30%, an 
admissible two-stage design indicates that 38 total patients will provide statistical power of 80% 
when controlling alpha at 10%. (Simon et al., 1989; Jung et al., 2004) The first stage (including 
patients from the safety lead-in) comprises 16 patients and if two or fewer responses (including 
immune related responses subsequent to initial PD) are seen in this group then the trial will stop 
early for futility. After completion of the second stage, 9 or more responses (not including 
immune related responses subsequent to initial PD) in 38 patients are required to reject the null 
hypothesis and conclude there is sufficient efficacy to warrant further study.
The primary endpoint for Cohort 3 is the tolerability of the combination of nivolumab, 
bevacizumab, and rucaparib based upon maintenance of dosing without drug modifications 

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within the first 100 days of dosing. A single stage design will be used to test the null hypothesis 
than the probability of modification within the first 100 days of dosing is 50% or greater. With 
15 patients in cohort 3, the study has 94% power to reject the null hypothesis at the 10% one-
sided type I error level if the probability of modification within the first 100 days of dosing is 
20% or less. 
The secondary endpoints for Cohort 3 will be to assess efficacy of the combination via objective 
response rate by RECIST 1.1. or modified GCIG CA-125 criteria.
13.2
Sample Size, Accrual Rate and Study Duration
The planned sample size for each cohort is 38 patients. The total sample size will be adjusted to 
allow for replacement of participants who never began protocol therapy for reasons including 
ineligibility, inevaluability, and participant drop out. Cohorts will accrue sequentially, with 
cohort 2 starting accrual after cohort 1 accrual is complete. Cohort 3 will include 15 patients. It is 
anticipated that approximately 6 patients will be enrolled per month for an approximate accrual 
period of 14 months for the first two cohorts. In cohort 3 it is anticipated that 15 patients will be 
accrued over 10 months and analysis will occur 100 days after the last patient is accrued. All 
patients who begin protocol therapy will be included in the evaluation of objective response and 
toxicity.
13.3
Stratification Factors
No stratification factors are planned.
13.4
Interim Monitoring Plan
The study includes a safety assessment lead-in for cohorts 1 and 2; please see section 13.1 for 
details.
Patients will be enrolled following a two-stage design with continuation of enrollment to the 
second stage if sufficient anti-tumor activity is seen in the first stage. The first stage for each 
cohort comprises 16 patients and if two or fewer responses (including immune related responses) 
are seen in this group then the cohort will stop early for futility.
Cohort 3 will use continuous monitoring for DLTs; please see section 13.1 for details.
13.5
Analysis of Primary Endpoints
The objective response rate (CR + PR) using RECIST 1.1 criteria will be reported with a 90% 
standard exact binomial confidence interval that does not adjust for the two-stage design.  This is 
chosen as a conservative estimation procedure considering the allowance of continuation to the 
second stage based on a secondary efficacy endpoint. 
Time-to-drug discontinuation or modification of any protocol treatment will be reported using 
the method of Kaplan-Meier, and the probability of discontinuation within 100 days will be 
presented with a one-sided 90% confidence interval (upper bound). Patients that discontinue 

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protocol therapy due to disease progression with no discontinuation or modification of any 
protocol treatment for toxicity will be censored at the time of disease progression. 
13.6
Analysis of Secondary Endpoints
Best overall response will be assessed among all patients who received at least one dose of both 
study drugs at the MTD. Best overall response will be estimated according to RECIST criteria as 
described in Section 11.1.4.4. Best overall immune related response and immune-related 
objective response rate will be estimated according to irRECIST criteria as described in Section 
11.1.7. composite response rate will be assessed using the modified composite endpoint (CR + 
PR, including immune related objective responses) and using modified GCIG CA-125 criteria as 
a secondary analysis, and each will be reported with 90% confidence intervals that do not adjust 
for the two-stage design.  
Time-to-event endpoints including duration of response, progression free survival and immune-
related progression free survival will be described using the method of Kaplan-Meier, and 
presented with 90% confidence intervals. Patients that are alive without disease progression at 
time of analysis are censored at the date of last disease evaluation.
Treatment-related toxicities will be summarized by maximum grade and by term using CTCAE 
v4.0 and reported with 90% binomial exact confidence intervals.
The association of baseline PD-L1 expression with anti-tumor activity will be evaluated using a 
Wilcoxon rank sum test of marker levels in responders versus non-responders using a one-sided 
alpha = 0.05.  With 20 or more patients evaluable at baseline for PD-L1 expression, there will be 
at least 80% power to detect a difference of 1.25 standardized units in PD-L1 expression.  
 
Analysis of exploratory biomarkers will be estimation-only, using summary statistics (such as 
mean, sd, median, IQR and range) to give the empirical distribution of marker levels detected at 
baseline and changes in marker levels during and after treatment in the subset of patients with 
paired specimen.  
13.7
Reporting and Exclusions
13.7.1 Evaluation of Toxicity
All participants will be evaluable for toxicity from the time of their first treatment.
13.7.2 Evaluation of the Primary Efficacy Endpoint
All of the participants who met the eligibility criteria and who receive at least one dose of 
study drug will be included in the main intent-to-treat analysis of the response rate. 
14. PUBLICATION PLAN
The results should be made public within 24 months of reaching the end of the study. The end of 
the study is the time point at which the last data items are to be reported, or after the outcome 

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data are sufficiently mature for analysis, as defined in the section on Sample Size, Accrual Rate 
and Study Duration. If a report is planned to be published in a peer-reviewed journal, then that 
initial release may be an abstract that meets the requirements of the International Committee of 
Medical Journal Editors. A full report of the outcomes should be made public no later than three 
(3) years after the end of the study. 

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

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APPENDIX B
SAFETY ALGORITHMS
 

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APPENDIX C
WHOLE BLOOD GENOTYPING SNP COLLECTION INSTRUCTIONS
SUPPLIES
6 mL K2 EDTA Vacutainer tube
1. Collect blood via direct venipuncture in a pre-labeled 6mL K2EDTA tube.   
2. Invert gently 8 times.
3. DO NOT CENTRIFUGE SAMPLE. 
4. Store samples in an upright position preferably in a-70ºC freezer (-20ºC is acceptable for 
short term storage).
A step down freezing process is recommended, if possible.  First, refrigerate the whole 
blood samples at 4°C for at least one day, but no longer than four days.  Then the samples 
should be placed upright in a -70°C freezer.
Holding samples longer than four days at 4°C may result in decreased recovery of high 
molecular weight DNA.
5. Complete the requisition and record the date and time of sample collection on the appropriate 
source document.
6. Batch ship samples on dry ice for processing per the shipment schedule. 

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APPENDIX D
SERUM SOLUBLE BIOMARKERS COLLECTION INSTRUCTIONS
SUPPLIES

8.5mL SST Vacutainer 

4 polypropylene tubes
1. Blood samples will be collected by direct venipuncture or through an indwelling catheter.  
If a catheter is used for blood collection, then approximately 1 mL of blood should be 
withdrawn initially and discarded.  Only saline is permitted to keep catheters patent, unless 
discussed and agreed upon by the Sponsor. If samples are obtained through a heparin lock, 
sufficient blood (~1 mL) must be withdrawn to remove the heparin solution.
2. To ensure sufficient sample volume for the required test is obtained, fill tube until 
vacuum is exhausted and blood ceases to flow.  
3. Immediately after collection, gently invert each blood sample 5 times and allow blood to 
clot for 30-45 minutes at room temperature (tube standing upright).
4. Centrifuge samples at room temperature for 10 minutes (swing out) or 15 minutes (fixed) 
at 1100-1300 x g until clot and serum are well separated.
5. Transfer serum equally from the 8.5mL SST into four appropriately labeled screw-capped 
polypropylene tubes.
6. Store the serum samples immediately (within 2 hours of collection) at approximately -
70C to ensure stability of the samples until they are shipped on dry ice per the shipment 
schedule.
If -70 freezer is not available, store at -20 and ship monthly on dry ice.
If a sample was not collected, do not send empty tube.