Conditions: Ovarian Cancer Triple-negative Breast Cancer Urothelial Carcinoma Solid Tumor
Allocation: NON_RANDOMIZED | Intervention model: PARALLEL
Enrollment: 25
Healthy volunteers: no

Brief summary:
This is an open label, Phase 1b/2 study with multiple treatment arms evaluating the safety, tolerability, pharmacokinetics (PK), and preliminary efficacy of rucaparib in combination with a second anticancer therapy in participants with an advanced/metastatic solid malignancy (Phase 1b), followed by evaluation of the combination in one or more specific participant populations in an expansion phase (Phase 2 cohorts).

Detailed description:

Arms:
arm 1: Participants will receive oral rucaparib twice daily (BID) and oral lucitanib once daily (QD) continuously in 28-day cycles. arm 2: Participants will receive oral rucaparib BID, administered continuously, in combination with intravenous (IV) sacituzumab govitecan administration on Day 1 and Day 8 of a 21-day cycle. arm 3: Participants will receive oral rucaparib QD, administered continuously, in combination with IV sacituzumab govitecan administration on Day 1 and Day 8 of a 21-day cycle.

Interventions: intervention 1: Rucaparib intervention 2: Lucitanib intervention 3: Sacituzumab govitecan
Intervention descriptions: intervention 1: Rucaparib will be administered per schedule specified in the arm description. intervention 2: Lucitanib will be administered per schedule specified in the arm description. intervention 3: Sacituzumab govitecan will be administered per schedule specified in the arm description.

Protocol document:
Prot_000.pdf: 
Clinical Study Protocol: CO-338-098 
Study Title: 
SEASTAR: A Phase 1b/2, Open-label, Parallel Arm Study to Assess the 
Safety, Tolerability, Pharmacokinetics, and Preliminary Efficacy of Oral 
Rucaparib in Combination with Other Anticancer Agents in Patients with a 
Solid Tumor  
Study Number: 
CO-338-098 
Study Phase: 
Phase 1b/2  
Product Names: 
Rucaparib (CO-338) 
Lucitanib (CO-3810) 
Sacituzumab Govitecan (IMMU-132; hRS7-SN38) 
M4344 
IND Number: 
 
EUDRA CT 
Number 
 
Indication: 
Advanced, recurrent, or metastatic solid tumors 
Investigators: 
Multicenter 
Sponsor Name: 
Clovis Oncology, Inc. 
Sponsor 
Address: 
 
 
Telephone Number:  
 
Facsimile Number: 
 
Responsible 
Medical Officer: 
 
Date 
 
 
 
 
Amendment 2.0 
01 September 2020 
Confidentiality Statement 
This document contains confidential information belonging to Clovis Oncology, Inc. Except 
as otherwise agreed to in writing, by accepting or reviewing this document, you agree to hold 
this information in confidence and not copy or disclose it to others (except where required by 
applicable law) or use it for unauthorized purposes. In the event of any actual or suspected 
breach of this obligation, Clovis Oncology, Inc., must be promptly notified. 
NCT #: NCT03992131


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PROTOCOL APPROVAL SIGNATURE PAGE 
Protocol: 
CO-338-098 
Title: 
SEASTAR: A Phase 1b/2, Open-label, Parallel Arm Study to Assess the 
Safety, Tolerability, Pharmacokinetics, and Preliminary Efficacy of Oral 
Rucaparib in Combination with Other Anticancer Agents in Patients 
with a Solid Tumor 
Date: 
01 September 2020 
Version: 
Amendment 2.0 
Reviewed and Approved by: 
Clovis Oncology, Inc. 
Clovis Oncology, Inc. 
Clovis Oncology, Inc. 
Clovis Oncology, Inc. 
DocuSign Envelope ID: C2550004-A6EF-422F-9E8C-2C26398F3C7A


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PROTOCOL ACCEPTANCE FORM 
Protocol: 
CO-338-098 
Title: 
SEASTAR: A Phase 1b/2, Open-label, Parallel Arm Study to Assess the 
Safety, Tolerability, Pharmacokinetics, and Preliminary Efficacy of Oral 
Rucaparib in Combination with Other Anticancer Agents in Patients 
with a Solid Tumor 
Date: 
01 September 2020 
Version: 
Amendment 2.0 
 
 
I have carefully read this protocol and agree that it contains all the necessary information 
required to conduct this study. I agree to conduct this study as described and according to 
the Declaration of Helsinki, ICH E6(R2) Guidelines for GCP, and all applicable regulatory 
requirements. 
 
 
 
 
 
Investigator’s Signature 
 
Date 
(DD-MMM-YYYY) 
 
 
 
 
 
Name (printed) 
 
 
 
 


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SPONSOR’S MEDICAL EXPERT FOR THE STUDY 
Medical Expert: 
 
 
 
Telephone: 
 
Facsimile:  
 
E-mail: 
 
 
Clinical Investigators, Study Sites, and Laboratories: 
This is a multicenter study. Information on investigators, institutions, and laboratories 
involved in the study are maintained in the clinical study file and can be provided upon 
request. 
 
 


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SYNOPSIS 
Sponsor 
Clovis Oncology, Inc. 
Name of Finished Products 
Rucaparib tablets; 
Lucitanib tablets; 
Sacituzumab govitecan for infusion; 
M4344 tablets 
Name of Active Ingredients (respectively) 
Rucaparib camsylate (CO-338); 
Lucitanib (CO-3810); 
Sacituzumab govitecan (IMMU-132); 
M4344 
Study Title 
SEASTAR: A Phase 1b/2, Open-label, Parallel Arm Study to Assess the Safety, 
Tolerability, Pharmacokinetics, and Preliminary Efficacy of Oral Rucaparib in 
Combination with Other Anticancer Agents in Patients with a Solid Tumor 
Study Number 
CO-338-098 
Study Phase 
Phase 1b/2 
Background and Study Rationale 
This study aims to evaluate the poly (adenosine diphosphate [ADP]-ribose) polymerase 
(PARP) inhibitor, rucaparib, in combination with various other anticancer agents that have 
a different mechanism of action.  
Rucaparib is an inhibitor of PARP enzymes, which play a critical role in base excision 
repair (BER) of deoxyribonucleic acid (DNA).1 When PARP function and effective BER 
are impaired, double-stranded DNA breaks accumulate. In cells deficient in homologous 
recombination, these breaks cannot be accurately repaired, resulting in synthetic lethality.2 
While mutated breast cancer genes (BRCA)1 and BRCA2 are most commonly associated 
with homologous recombination deficiency (HRD), other homologous recombination 
repair (HRR) proteins may be mutated or functionally deficient in ovarian and other 
cancers. Rucaparib (Rubraca®) is approved in the United States (US) as monotherapy 
treatment for adult patients with deleterious BRCA mutation (germline and/or somatic)-
associated epithelial ovarian (EOC), fallopian tube (FTC), or primary peritoneal (PPC) 
cancer who have been treated with 2 or more prior chemotherapies, and for the 
maintenance treatment of adult patients with recurrent EOC, FTC, or PPC who have a 
complete or partial response to platinum-based chemotherapy.3 Rucaparib is also approved 
in the European Union (EU) as monotherapy treatment of adult patients with platinum-


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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.4 In 
addition, rucaparib is being developed for the treatment of cancer associated with HRD, 
defined by the presence of a deleterious mutation in BRCA1, BRCA2, or other HRR 
genes, and/or high percentage of tumor genome with loss of heterozygosity (LOH), which 
is a phenotypic consequence of HRD. 
PARP inhibitors have been explored in combination with chemotherapy; however, such 
combinations were challenging to administer due to overlapping toxicity, specifically 
myelosuppression, therefore novel combination approaches with more selective targeted 
agents are currently thought to have more potential. Combination therapy with a PARP 
inhibitor would aim to increase accumulation of DNA damage and subsequent dependence 
on HRR, such as in the combination of a PARP inhibitor with a topoisomerase inhibitor. 
Agents that inhibit topoisomerase 1, including irinotecan and topotecan, have 
demonstrated synergy with PARP inhibitors in a variety of human tumor cell lines, 
including ovarian and breast cancers.5,6 The PARP inhibitor olaparib has been shown to 
potentiate the cytotoxicity of SN-38, the active metabolite of irinotecan and topotecan, 
irrespective of mismatch repair (MMR) status in a variety of MMR-deficient or MMR-
efficient cell lines.7 A clinical study of the PARP inhibitor veliparib combined with 
topotecan showed a mechanistic interaction between the 2 drugs, resulting in delayed 
repair of Topo1-mediated DNA damage, despite there being some challenges with 
overlapping hematologic toxicities.8 Targeted delivery of SN-38 to cancer cells through 
administration of an antibody-drug conjugate (ADC) has greater potential for combination 
therapy with a PARP inhibitor by reducing off-target and additive toxicity. Other 
combinations would aim to induce a BRCA-like phenotype in order to elicit PARP 
inhibitor and BRCA-like synthetic lethality, as has been shown to occur in combinations 
between PARP inhibitors and angiogenesis inhibitors (such as vascular endothelial growth 
factor [VEGF] inhibitors) and ataxia telangiectasia mutated and Rad3-related (ATR) 
inhibitors. The combination of a PARP inhibitor with a VEGF inhibitor, which have 
distinctly different mechanisms of action, have also demonstrated synergistic effects in 
nonclinical studies (Clovis Oncology, data on file). In addition, a Phase 2 clinical study in 
patients with recurrent ovarian cancer treated with the PARP inhibitor, olaparib, and an 
antiangiogenic agent, cediranib, has shown promise.9 Nonclinical data indicate that ATR 
inhibition increases sensitivity to PARP inhibition10 and that defects in ATR signaling may 
result in synthetic lethality with PARP inhibition.11 Inhibition of ATR may also be a 
mechanism to overcome primary and acquired resistance to PARP inhibition. 
This study will initially evaluate rucaparib in combination with 3 other anticancer 
therapies; additional combinations may be added at a later date.  
The initial 3 Treatment Arms include the following: 
Treatment Arm A: rucaparib and lucitanib; lucitanib is a potent, selective inhibitor of 
the tyrosine kinase activity of vascular endothelial growth factor 
receptors, types 1, 2, and 3 (VEGFR1–3); platelet-derived growth factor
receptors (PDGFR), types alpha and beta (PDGFRα/β); and fibroblast 
growth factor receptors (FGFR), types 1, 2, and 3 (FGFR1-3). 


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Treatment Arm B: rucaparib and IMMU-132 (sacituzumab govitecan); sacituzumab 
govitecan is an antibody-drug conjugate comprised of a humanized 
antibody targeting Trop-2 (trophoblast cell-surface antigen-2) linked 
to SN-38, a potent topoisomerase 1 inhibitor.  
Treatment Arm C:  rucaparib and M4344; M4344 is a potent ATR inhibitor.  
The rucaparib combinations selected for evaluation within this study were carefully chosen 
based on nonclinical and clinical data, and theoretical concepts to support a potential 
efficacious synergism. The rationale for each rucaparib combination is provided in the 
body of the protocol. 
Primary Objectives: 
Phase 1b of each Treatment Arm 
• To evaluate the safety and tolerability of rucaparib in combination with a second 
anticancer agent and to determine the maximum tolerated dose (MTD) and/or the 
recommended Phase 2 dose (RP2D) of the combination. 
Phase 2 of each Treatment Arm 
• To evaluate the efficacy of rucaparib in combination with a second anticancer agent 
by measuring investigator-assessed confirmed best overall response rate (ORR) by 
Response Evaluation Criteria in Solid Tumors (RECIST) Version (v)1.1 in one or 
more expansion cohorts evaluating the combination. 
Secondary Objectives: 
Phase 1b of each Treatment Arm 
• To characterize the pharmacokinetics (PK) of rucaparib (Treatment Arm A and 
Treatment Arm C) and the second anticancer agent (all treatment arms), as well as 
the metabolites for the second anticancer agent (Treatment Arm B) when rucaparib 
and the second anticancer agent are co-administered. 
• To evaluate the preliminary efficacy of rucaparib in combination with a second 
anticancer agent in various solid tumors. 
Phase 2 of each Treatment Arm 
• To evaluate the safety and tolerability of rucaparib in combination with a second 
anticancer agent. 
• To evaluate progression-free survival (PFS) in one or more expansion cohorts. 
• To evaluate duration of response (DOR) in one or more expansion cohorts. 
Exploratory Objectives: 
• To assess tumor tissue biomarkers that correlate with response to the combination. 
• To evaluate circulating cell-free tumor DNA (ctDNA) as a molecular marker of 
response to the combination. 
• To evaluate biomarkers associated with resistance to the combination. 


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• To assess genomic changes over time in plasma and tumor samples. 
• To determine steady-state exposure of rucaparib and the second anticancer agent 
(all treatment arms) by sparse PK sampling. 
• To evaluate the development of antidrug antibodies (ADAs) (Treatment Arm B).  
• To characterize the PK of metabolites of the second anticancer agent (Treatment 
Arm C) when rucaparib and the second anticancer agent are co-administered. 
Study Design 
This is a Phase 1b/2, open-label, study with multiple treatment arms evaluating the safety, 
tolerability, PK, and preliminary efficacy of rucaparib in combination with a second 
anticancer therapy in patients with an advanced/metastatic solid malignancy (Phase 1b), 
followed by evaluation of the combination in one or more specific patient populations in 
an expansion phase (Phase 2 cohorts). 
The description of the study design provided in this synopsis is general across all treatment 
arms. The specifics of each treatment arm are included in the body of the protocol. 
Screening Phase 
All patients will undergo screening assessments prior to enrollment. Patients will be 
required to provide archival tumor tissue or a more recently obtained tissue sample, as well 
as blood samples, for genomic analysis. Enrollment of eligible patients is described below.  
Treatment Phase  
Treatment cycles will be 21 or 28 days in length, depending upon the study drug 
combination; cycles are defined within each specific treatment arm. All patients will be 
monitored for safety throughout the treatment phase.  In addition, all patients will be 
assessed for disease status per RECIST v1.1 per the time interval specified within each 
treatment arm until one of the following: radiological disease progression as assessed by 
the investigator, death, loss to follow-up, withdrawal from study, study termination, or 
initiation of subsequent anticancer treatments.  
Phase 1b/ Dose-escalation Phase:  
In the Phase 1b portion of each treatment arm, there will be an estimated 6 to 12 
dose-escalation cohorts, with a minimum of 3 patients enrolled in each cohort, followed by 
an expanded evaluation of the RP2D in up to 10 additional patients. 
This portion of the study will enroll patients with advanced malignancy who have relapsed 
following prior treatment or are not eligible for standard of care treatment. Dose escalation 
will follow a 3+3 design. The starting doses and dose escalation steps are defined for each 
separate treatment arm within the body of the protocol. 
Dose-limiting toxicities (DLTs) are defined according to criteria specified for each 
combination treatment within the body of the protocol. DLTs will be assessed by the 
investigator based on toxicity grade (according to the National Cancer Institute Common 
Terminology Criteria for Adverse Events [NCI CTCAE] v5.0), clinical significance, and 
possible relationship to either or both study drug(s) The MTD is defined as the maximum 
dose combination at which < 33% of patients experience a DLT during Cycle 1 (DLT-


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evaluation period). If a DLT is observed in 1 of 3 patients, then 3 additional patients will 
be enrolled at that same dose level. Dose escalation will continue until at least 2 of the 3 to 
6 patients treated at a dose level experience a DLT or until the maximum dose to be 
evaluated is reached, whichever occurs first. If the end of dose escalation is reached due to 
DLTs, the next lower dose will then be considered the MTD. Alternatively, if the 
difference between the MTD and the maximally delivered dose is significant (such as 
100%), then a more modestly de-escalated dose may be explored (eg, 20% to 50%). 
Prior to initiating treatment at each new combined dose level or prior to expanding a 
cohort, a safety teleconference will be held to review patient data, including, but not 
limited to, demographics, PK results, study drug combination dosing, concomitant 
medications, hematology and chemistry, and adverse events (AEs), and then confer and 
document agreement that dose escalation and/or expanding an existing dose level is/are 
considered appropriately safe. Safety teleconferences will include study investigators, the 
sponsor’s medical monitor, and may include other representatives or designees of the 
sponsor and the study sites. 
The RP2D for evaluation in the Phase 2 portion will be selected based on overall safety 
and tolerability, PK, as well as any efficacy, if observed. The RP2D may or may not be the 
same as the MTD identified in the dose-escalation. For example, if the MTD is not 
reached, if exposure at the MTD is much higher than the level believed to be required for 
efficacy, or if subsequent cycles of treatment provide additional insight on the safety 
profile of the combination, then the RP2D may be a different, although not higher, dose 
than the MTD for the combination. Once the RP2D of the combination has been 
provisionally determined, up to 10 additional Phase 1b patients may be enrolled and 
treated at the RP2D, in order to further characterize safety, tolerability, and PK and to 
confirm that this is the optimal dose combination to evaluate in Phase 2. 
Phase 2/ Expansion Phase: 
Phase 2 of each treatment arm will not commence until the RP2D has been established in 
Phase 1b. In Phase 2, the study drug combination administered at the RP2D will be 
evaluated for safety and tolerability, PK, pharmacodynamics, and efficacy in patients as 
defined for each treatment arm and cohort. 
Phase 2 will enroll patients into specified cohorts for each treatment combination, and a 
Simon 2-stage design12 will be utilized for each of the planned Phase 2 expansion cohorts.  
End of Treatment and Follow-up 
Upon treatment discontinuation in either Phase 1b or Phase 2, regardless of reason (with 
the exception of patient withdrawal or death), patients will have an End of Treatment Visit, 
and all patients will be followed for at least 28 days after the last dose of study drug. 
Patients who discontinue treatment for a reason other than disease progression or death 
should continue to have tumor scans performed at the interval specified for that treatment 
arm until radiological disease progression as assessed by the investigator, death, loss to 
follow-up, withdrawal from study, study termination, or initiation of subsequent anticancer 
treatments. 
The study will be considered ongoing until all patients have either met one of the 


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withdrawal criteria (see below) or have withdrawn consent for the study, or the sponsor 
terminates the study. 
Number of Patients 
The number of patients anticipated to participate in each treatment arm is variable due to 
the uncertainty in the number of dose escalation cohorts in Phase 1b and the design in 
Phase 2. Sample size estimates for Phase 1b and each cohort in Phase 2 are provided in the 
body of the protocol for each treatment arm. 
For Treatment Arm A, total enrollment is anticipated to be up to 135 patients, with up to 
55 patients in Phase 1b and up to 80 patients in Phase 2. 
For Treatment Arm B, total enrollment is anticipated to be up to 194 patients, with up to 
55 patients in Phase 1b and up to 139 patients in Phase 2. 
For Treatment Arm C, total enrollment is anticipated to be up to 135 patients with up to 
55 patients in Phase 1b and up to 80 patients in Phase 2. 
Number of Sites 
Three to six sites in the US are expected to participate in the Phase 1b portion of the study; 
approximately 25 sites globally may be activated to participate in the Phase 2 portion of 
the study. 
Enrollment and Study Treatment 
In Phase 1b, eligible patients will be enrolled into cohorts as described above. Enrollment 
in the Phase 2 portion will be competitive for all treatment arms. If a patient appears to be 
eligible for more than one treatment arm that is open to enrollment, the investigator will be 
responsible for selecting the most appropriate treatment arm for the patient. 
Patients participating in this study will enroll into either the Phase 1b or Phase 2 portion, 
but a patient cannot participate in both portions of the same treatment arm. No 
randomization or blinding is planned in the study. 
Patients will be treated with the study drug combination at the doses specified by the 
Phase 1b dose escalation plan for each combination or the RP2D. Rucaparib will be 
administered twice a day (BID) continuously up to a maximum dose of 600 mg BID, and 
the other study drug will be administered as specified within each respective treatment 
arm. 
Withdrawal Criteria 
A patient must be discontinued from treatment with study drug if any of the following 
apply: 
• 
Consent withdrawal at the patient's own request or at the request of their legally 
authorized representative. 
• 
Progression of patient's underlying disease by RECIST v1.1 as assessed by the 
investigator, unless patient is still receiving benefit from the study drug(s) 
according to the investigator, and the patient has provided additional consent. 


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• 
Initiation of any other anticancer therapy. 
• 
Any event, adverse or otherwise, that, in the opinion of the investigator, would 
pose an unacceptable safety risk to the patient. If it is determined that 1 of the 
study drugs in the combination is posing a safety risk and that study drug is 
permanently discontinued, administration of the other study drug may continue if 
none of the other withdrawal criteria have been met and the investigator believes 
that the patient may continue to receive benefit. 
• 
Any concomitant illness that, in the opinion of the investigator, would affect 
assessments of the clinical status to a significant degree and requires 
discontinuation of therapy. 
• 
A positive pregnancy test at any time during the study. 
Efficacy Assessments 
Tumor assessment measurements will be performed at screening and at treatment 
arm-specified intervals until objective radiological disease progression. Tumor 
assessments should be performed at the time of treatment discontinuation if the reason for 
discontinuation was other than radiologically-confirmed disease progression and the time 
elapsed since the last assessment is greater than the tumor-assessment interval. Additional 
tumor assessments should be performed as clinically indicated. Confirmatory scans should 
be obtained no less than 4 weeks after the initial response.  
Disease assessment will comprise clinical examination and appropriate imaging techniques 
per RECIST v1.1 (computed tomography and/or magnetic resonance imaging scans of the 
chest, abdomen, and pelvis with appropriate slice thickness per RECIST v1.1). Other 
complementary assessments (X-ray, positron emission tomography [PET], and ultrasound) 
may be performed if required. Tumor markers should be collected as clinically indicated 
for the response assessment by RECIST v1.1. For example, a complete response (CR) in 
an ovarian cancer patient would require normalization of cancer antigen-125 (CA-125). 
Tumor response will be interpreted using RECIST v1.1. Disease progression will be 
determined by RECIST v1.1. If the radiologic assessment does not confirm disease 
progression, patients should continue on treatment and continue to be assessed by 
RECIST v1.1 per the protocol schedule of assessments. 
Patients who discontinue treatment for a reason other than disease progression or death 
should continue to have tumor scans performed at the interval specified for that treatment 
arm until radiological disease progression as assessed by the investigator, death, loss to 
follow-up, withdrawal from study, study termination or specific cohort closure (in 
Phase 2), or initiation of subsequent anticancer treatments. 
Safety Assessments 
Safety and tolerability will be assessed based on the following: 
• Incidence, type, seriousness, severity, and causality of AEs reported (CTCAE v5.0); 
• Clinical laboratory investigations (hematology, chemistry, urinalysis); 


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• Vital signs (blood pressure, heart rate, and body temperature); 
• 12-lead electrocardiograms (ECGs); 
• Physical examinations; and 
• Eastern Cooperative Oncology Group (ECOG) performance status. 
Pharmacokinetic Assessments 
Samples for intensive (Phase 1b, Cycle 1) and sparse (Phase 1b and Phase 2) PK 
assessments will be collected for both study drugs in the combination, with the exception 
of no intensive rucaparib PK collection in Treatment Arm B. 
Statistical Methods 
Sample Size  
The number of patients anticipated to participate in each treatment arm is variable due to 
the uncertainty in the number of dose escalation cohorts in Phase 1b and the design in 
Phase 2.  
Each Phase 2 cohort will be evaluated for futility with the option to stop enrollment in the 
cohort if the prespecified outcomes are not observed. Sample size estimates for Phase 1b 
and each cohort in Phase 2 are provided in the body of the protocol for each treatment arm. 
Efficacy Analysis  
The analysis of all efficacy endpoints will be based on the RECIST v1.1 criteria as 
assessed by the investigator. 
Primary Efficacy Endpoint 
The primary efficacy endpoint for each cohort in Phase 2: 
• Objective response. 
Confirmed ORR is defined as the proportion of patients with a documented and confirmed 
best overall response of CR or partial response (PR) as assessed by the investigator. A 
confirmed CR or PR is a response that is maintained and documented on a subsequent 
tumor assessment no less than 4 weeks after initial response. The frequency and 
percentages of patients with a best overall response of CR, PR, stable disease (SD), or 
progressive disease (PD) will be summarized. ORR (confirmed CR + PR) will also be 
summarized with frequencies and percentages. All summaries of response rate will be 
accompanied by 95% confidence intervals (CIs). 
Secondary Efficacy Endpoints 
The secondary efficacy endpoints are as follows: 
• Duration of response (DOR; Phase 2), 
• Progression-free survival (PFS; Phase 2),  
• Objective response (Phase 1b). 
PFS will be calculated as 1+ the number of days from the first dose of study drug to 
documented radiographic progression, according to RECIST v1.1, as determined by the 


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investigator, or death due to any cause, whichever occurs first. Patients without a 
documented event of radiographic progression will be censored on the date of their last 
adequate tumor assessment (ie, radiologic assessment), or date of first dose of study drug if 
no post-baseline tumor assessments have been performed. Only tumor scans prior to start 
of any subsequent anticancer treatment are included. 
For any Phase 2 patient who reached a best response of CR or PR, DOR will be measured 
from the date that best response is first recorded until the first date that PD is documented 
per RECIST v1.1. DOR will be summarized as a time to event variable. For patients who 
continue treatment post-progression, the first date of progression will be used for the 
analysis. Patients without a documented event of radiographic progression will be censored 
on the date of the last adequate tumor assessment. 
For both PFS and DOR, the Kaplan-Meier methodology will be used. If able to be 
estimated, the 50th (median) percentile together with a 95% CI, will be presented. The 
number of patients with events and the number of patients at risk at each timepoint will be 
presented, and censored patients will be graphically displayed. 
Safety Analyses 
All safety analyses will be summarized for the Safety Population separately for each 
treatment arm. Within a treatment arm, safety analyses will be summarized by dose cohort 
and pooled for all patients in Phase 1b and by expansion cohort in Phase 2. Safety and 
tolerability will be assessed based on the following: 
• 
DLTs in the dose-escalation (Phase 1b) portion; 
• 
Incidence, type, seriousness, severity, and causality of AEs reported; 
• 
Clinical laboratory investigations 
• 
Vital signs; 
• 
12-lead ECGs; 
• 
Physical examinations;  
• 
ECOG performance status. 
Pharmacokinetic Analyses 
In the Phase 1b portion, blood sampling for PK analyses of both rucaparib and the second 
study drug will be conducted in all patients. The PK parameters will be determined using 
non-compartmental methods. Pharmacokinetic parameters, including but not limited to 
Cmax, Cmin, tmax, AUC0-last, AUC0-inf, Vss/F, and CL/F, will be calculated and reported as 
data allow. 
Date of Protocol Amendment 2.0 Approval 
01 September 2020 
 
 


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TABLE OF CONTENTS 
PROTOCOL APPROVAL SIGNATURE PAGE .....................................................................2 
PROTOCOL ACCEPTANCE FORM .......................................................................................3 
SPONSOR’S MEDICAL EXPERT FOR THE STUDY ...........................................................4 
SYNOPSIS .................................................................................................................................5 
LIST OF IN-TEXT TABLES ..................................................................................................21 
LIST OF APPENDICES ..........................................................................................................22 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS ..........................................23 
1 
INTRODUCTION ...........................................................................................................30 
1.1 
Background ............................................................................................................30 
1.1.1 
Rucaparib .....................................................................................................30 
1.1.1.1 
Nonclinical Experience ......................................................................31 
1.1.1.2 
Clinical Experience ............................................................................31 
1.2 
Rationale for the Study ..........................................................................................35 
2 
STUDY OBJECTIVES ....................................................................................................36 
2.1 
Primary Objective ..................................................................................................36 
2.2 
Secondary Objectives.............................................................................................36 
2.3 
Exploratory Objectives ..........................................................................................37 
3 
STUDY DESIGN.............................................................................................................38 
3.1 
Overall Study Design and Plan ..............................................................................38 
3.1.1 
Screening Phase ...........................................................................................38 
3.1.2 
Enrollment....................................................................................................39 
3.1.3 
Treatment Phase ...........................................................................................39 
3.1.3.1 
Phase 1b .............................................................................................40 
3.1.3.2 
Phase 2 ...............................................................................................42 
3.1.4 
End of Treatment and Safety Follow-up ......................................................43 
3.2 
Removal of Patients from Therapy or Assessment ................................................43 
3.3 
End of Study ..........................................................................................................44 
4 
OVERALL STUDY POPULATION SELECTION ........................................................44 
4.1 
All Patients or All Partners of Patients of Reproductive Potential ........................44 
4.2 
Waivers of Inclusion/Exclusion Criteria ................................................................45 
5 
RUCAPARIB TREATMENT .........................................................................................46 
5.1 
Rucaparib Description of Treatment and Storage ..................................................46 
5.2 
Rucaparib Packaging and Labeling .......................................................................46 
5.3 
Blinding/Masking of Treatments ...........................................................................46 
5.4 
Method of Assigning Patients to Treatment Arms ................................................46 
5.5 
Preparation and Administration of Rucaparib .......................................................47 
5.6 
Dose Modification Criteria for Rucaparib Combinations ......................................47 


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5.7 
Treatment Compliance ...........................................................................................47 
5.8 
Accountability of Protocol-specified Treatment ....................................................48 
5.9 
Investigational Treatment beyond Disease Progression ........................................48 
6 
PRIOR AND CONCOMITANT THERAPY ..................................................................49 
6.1 
Supportive Care .....................................................................................................49 
6.2 
Radiotherapy ..........................................................................................................49 
6.3 
Anticancer or Experimental Therapy .....................................................................49 
6.4 
CYP450 Isoenzyme Inhibitors, Inducers, and Substrates ......................................49 
6.5 
Anticoagulants .......................................................................................................50 
6.6 
Other Concomitant Medications ............................................................................50 
6.7 
Imaging Restrictions and Precautions ....................................................................50 
6.8 
General Restrictions ...............................................................................................51 
7 
METHODS OF DATA COLLECTION ..........................................................................51 
7.1 
Medical History and Demographic/ Baseline Characteristics ...............................51 
7.2 
Prior and Concomitant Medication Assessments ..................................................51 
7.3 
Efficacy Evaluations ..............................................................................................51 
7.3.1 
Disease/ Tumor Assessments .......................................................................51 
7.4 
Safety Evaluations .................................................................................................52 
7.4.1 
Adverse Event Assessment ..........................................................................52 
7.4.2 
Clinical Laboratory Investigations ...............................................................53 
7.4.3 
Vital Signs ....................................................................................................54 
7.4.4 
12-Lead Electrocardiogram .........................................................................54 
7.4.5 
Physical Examinations, Body Weight, and Height ......................................54 
7.4.6 
ECOG Performance Status ..........................................................................55 
7.5 
Biomarker Evaluations...........................................................................................55 
7.5.1 
Mandatory Tumor Tissue Analysis ..............................................................55 
7.5.2 
Plasma ctDNA Analysis ..............................................................................56 
7.5.3 
Pharmacogenomics ......................................................................................56 
7.5.4 
Additional Research .....................................................................................56 
7.6 
Other Study Evaluations ........................................................................................56 
8.A TREATMENT ARM A: RUCAPARIB AND LUCITANIB ..........................................57 
 Angiogenesis Inhibition .........................................................................................57 
 Lucitanib Background ............................................................................................58 
8.A.2.1 
Mechanism of Action of Lucitanib ..............................................................58 
8.A.2.2 
Nonclinical Experience ................................................................................58 
8.A.2.3 
Clinical Experience ......................................................................................59 
8.A.2.3.1 
Clinical Pharmacology .......................................................................59 
8.A.2.3.2 
Efficacy ..............................................................................................60 
8.A.2.3.3 
Safety .................................................................................................60 


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 Rationale for Rucaparib and Lucitanib Combination ............................................61 
8.A.3.1 
Dose and Duration Rationale .......................................................................62 
8.A.3.2 
Expansion Cohorts Rationale .......................................................................63 
 Treatment Arm A Study Design ............................................................................63 
8.A.4.1 
Treatment Arm A Screening and Enrollment ..............................................64 
8.A.4.2 
Treatment Arm A: Treatment Phase ............................................................64 
8.A.4.2.1 
Phase 1b .............................................................................................65 
8.A.4.2.2 
Phase 2 Cohorts..................................................................................67 
8.A.4.3 
End of Treatment Arm A (both Phases) and Safety Follow-up ...................67 
 Study Population Selection for Treatment Arm A .................................................68 
8.A.5.1 
Treatment Arm A: Number of Patients and Sites ........................................68 
8.A.5.2 
Treatment Arm A: Inclusion Criteria ...........................................................68 
8.A.5.3 
Treatment Arm A Exclusion Criteria ...........................................................70 
8.A.5.4 
Patients or Partners of Patients of Reproductive Potential ..........................72 
 Study Treatment(s): Treatment Arm A ..................................................................72 
8.A.6.1 
Investigational Drug Product – Lucitanib ....................................................72 
8.A.6.2 
Lucitanib Packaging and Labeling...............................................................72 
8.A.6.3 
Preparation and Administration of Lucitanib ..............................................72 
8.A.6.4 
Dose Modification and Retreatment Criteria for Rucaparib and 
Lucitanib ......................................................................................................73 
8.A.6.4.1 
Management of New or Worsening Pulmonary Symptoms ..............77 
8.A.6.4.2 
Rucaparib and/or Lucitanib Dose Reductions ...................................77 
8.A.6.4.3 
Rucaparib and/or Lucitanib Discontinuation .....................................78 
8.A.6.5 
Management of Adverse Events Specific to Lucitanib................................78 
8.A.6.5.1 
Management of Treatment-emergent Hypertension ..........................78 
8.A.6.5.2 
Management of Treatment-emergent Proteinuria ..............................82 
8.A.6.5.3 
Management of Subclinical Hypothyroidism ....................................83 
8.A.6.5.4 
Management of Decrease in Left Ventricular Ejection Fraction .......83 
8.A.6.5.5 
Management of Posterior Reversible Encephalopathy Syndrome .....84 
8.A.6.6 
Treatment Arm A Study Drug Compliance and Accountability .................84 
 Prior and Concomitant Therapy .............................................................................84 
8.A.7.1 
Other Concomitant Medications ..................................................................84 
 Study Procedures and Methods for Treatment Arm A ..........................................85 
8.A.8.1 
Schedule of Assessments:  Treatment Arm A .............................................85 
8.A.8.2 
Methods of Data Collection: Arm A ............................................................90 
8.A.8.2.1 
Left Ventricular Ejection Fraction Assessment .................................90 
8.A.8.2.2 
Additional Clinical Laboratory Investigations...................................90 
8.A.8.2.3 
Pharmacokinetic Sample Collection ..................................................90 
 Planned Statistical Methods: Treatment Arm A ....................................................91 
8.A.9.1 
Determination of Sample Size .....................................................................91 
8.B TREATMENT ARM B: RUCAPARIB AND SACITUZUMAB GOVITECAN ...........93 


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 Antibody-drug Conjugates .....................................................................................93 
 Sacituzumab Govitecan Background .....................................................................93 
8.B.2.1 
Mechanism of Action of Sacituzumab Govitecan .......................................94 
8.B.2.2 
Nonclinical Experience ................................................................................94 
8.B.2.2.1 
Pharmacology ....................................................................................94 
8.B.2.2.2 
Pharmacokinetics ...............................................................................95 
8.B.2.2.3 
Toxicology .........................................................................................95 
8.B.2.3 
Clinical Experience ......................................................................................95 
8.B.2.3.1 
Efficacy ..............................................................................................96 
8.B.2.3.2 
Safety .................................................................................................97 
8.B.2.3.3 
Pharmacokinetics and Immunogenicity .............................................97 
 Rationale for Rucaparib and Sacituzumab Govitecan Combination .....................98 
8.B.3.1 
Dose and Duration Rationale .......................................................................98 
8.B.3.2 
Expansion Cohorts Rationale .......................................................................99 
 Treatment Arm B Study Design ............................................................................99 
8.B.4.1 
Treatment Arm B: Screening and Enrollment .............................................99 
8.B.4.2 
Treatment Arm B: Treatment Phase ..........................................................100 
8.B.4.2.1 
Phase 1b ...........................................................................................101 
8.B.4.2.2 
Phase 2 Cohort .................................................................................103 
8.B.4.3 
End of Treatment Arm B and Safety Follow-up ........................................103 
 Study Population Selection for Treatment Arm B ...............................................103 
8.B.5.1 
Treatment Arm B: Number of Patients and Sites ......................................103 
8.B.5.2 
Treatment Arm B: Inclusion Criteria .........................................................104 
8.B.5.3 
Treatment Arm B Exclusion Criteria .........................................................106 
8.B.5.4 
Patients or Partners of Patients of Reproductive Potential ........................108 
 Study Treatment(s): Arm B .................................................................................108 
8.B.6.1 
Investigational Drug Product – Sacituzumab Govitecan ...........................108 
8.B.6.2 
Sacituzumab Govitecan Packaging and Labeling ......................................109 
8.B.6.3 
Preparation and Administration of Sacituzumab Govitecan ......................109 
8.B.6.3.1 
Preparation .......................................................................................109 
8.B.6.3.2 
Preventative Medications .................................................................110 
8.B.6.3.3 
Vital Signs ........................................................................................111 
8.B.6.3.4 
Intravenous Administration of Sacituzumab Govitecan ..................111 
8.B.6.4 
Dose Modification and Retreatment Criteria for Rucaparib 
and Sacituzumab Govitecan .......................................................................111 
8.B.6.4.1 
Management of New or Worsening Pulmonary Symptoms ............117 
8.B.6.4.2 
Rucaparib and/or Sacituzumab Govitecan Dose Reduction ............117 
8.B.6.4.3 
Rucaparib and/or Sacituzumab Govitecan Discontinuation ............118 
8.B.6.5 
Management of Adverse Events Specific to Sacituzumab Govitecan .......118 
8.B.6.5.1 
Infusion-related Reactions ...............................................................118 
8.B.6.5.2 
Nausea, Vomiting, and Diarrhea ......................................................119 
8.B.6.5.3 
Neutropenia ......................................................................................120 


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8.B.6.6 
Treatment Arm B Study Drug Compliance and Accountability ................120 
 Prior and Concomitant Therapy ...........................................................................121 
8.B.7.1 
Immunosuppressive Agents .......................................................................121 
8.B.7.2 
Other Concomitant Medications ................................................................121 
 Study Procedures and Methods for Treatment Arm B.........................................121 
8.B.8.1 
Schedule of Assessments: Treatment Arm B.............................................121 
8.B.8.2 
Methods of Data Collection: Treatment Arm B ........................................127 
8.B.8.2.1 
Biomarker Analyses .........................................................................127 
8.B.8.2.2 
Pharmacokinetic and Immunogenicity Evaluations.........................127 
8.B.8.2.3 
Rucaparib Pharmacokinetic Sample Collection...............................127 
8.B.8.2.4 
Sacituzumab govitecan Pharmacokinetic Sample Collection ..........127 
8.B.8.2.5 
Sacituzumab govitecan Immunogenicity Assessments ...................128 
 Planned Statistical Methods: Treatment Arm B ..................................................128 
8.B.9.1 
Determination of Sample Size ...................................................................128 
8.C TREATMENT ARM C: RUCAPARIB AND M4344 ..................................................131 
 Ataxia telangiectasia mutated and Rad3-related (ATR) Inhibition .....................131 
 M4344 Background .............................................................................................131 
8.C.2.1 
Mechanism of Action of M4344 ................................................................131 
8.C.2.2 
Nonclinical Experience ..............................................................................132 
8.C.2.2.1 
Nonclinical Pharmacology ...............................................................132 
8.C.2.2.2 
Nonclinical Pharmacokinetics .........................................................132 
8.C.2.2.3 
Toxicology .......................................................................................133 
8.C.2.3 
Clinical Experience ....................................................................................133 
8.C.2.3.1 
Clinical Pharmacology .....................................................................133 
8.C.2.3.2 
Efficacy ............................................................................................134 
8.C.2.3.3 
Safety ...............................................................................................134 
 Rationale for Rucaparib and M4344 Combination ..............................................136 
8.C.3.1 
Dose and Duration Rationale .....................................................................136 
8.C.3.2 
Expansion Cohorts Rationale .....................................................................137 
 Treatment Arm C Study Design ..........................................................................138 
8.C.4.1 
Treatment Arm C Screening and Enrollment ............................................138 
8.C.4.2 
Treatment Arm C: Treatment Phase ..........................................................139 
8.C.4.2.1 
Phase 1b ...........................................................................................139 
8.C.4.2.2 
Phase 2 Cohorts................................................................................141 
8.C.4.3 
End of Treatment Arm C and Safety Follow-up ........................................142 
 Study Population Selection for Arm C ................................................................142 
8.C.5.1 
Treatment Arm C: Number of Patients and Sites ......................................142 
8.C.5.2 
Treatment Arm C: Inclusion Criteria .........................................................143 
8.C.5.3 
Treatment Arm C Exclusion Criteria .........................................................144 
8.C.5.4 
Patients or Partners of Patients of Reproductive Potential ........................145 
 Study Treatment(s): Arm C .................................................................................145 


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8.C.6.1 
Investigational Drug Product – M4344......................................................146 
8.C.6.2 
M4344 Packaging and Labeling ................................................................146 
8.C.6.3 
Preparation and Administration of M4344 ................................................146 
8.C.6.4 
Dose Modification and Retreatment Criteria for Rucaparib and M4344 ..146 
8.C.6.4.1 
Management of New or Worsening Pulmonary Symptoms ............152 
8.C.6.4.2 
Rucaparib and/or M4344 Dose Reduction .......................................152 
8.C.6.4.3 
Rucaparib and/or M4344 Discontinuation .......................................153 
8.C.6.5 
Treatment Arm C Study Drug Compliance and Accountability ................153 
 Prior and Concomitant Therapy ...........................................................................153 
8.C.7.1 
Other Concomitant Medications ................................................................154 
 Study Procedures and Methods for Treatment Arm C.........................................154 
8.C.8.1 
Schedule of Assessments: Treatment Arm C.............................................154 
8.C.8.2 
Methods of Data Collection: Arm C ..........................................................160 
8.C.8.2.1 
Pharmacokinetic Sample Collection ................................................160 
8.C.8.2.2 
Pharmacodynamic Sample Collection .............................................160 
 Planned Statistical Methods: Treatment Arm C ..................................................160 
8.C.9.1 
Determination of Sample Size ...................................................................161 
9 
PLANNED STATISTICAL METHODS: ALL TREATMENT ARMS .......................163 
9.1 
General Considerations ........................................................................................163 
9.2 
Analysis Populations ............................................................................................163 
9.3 
Demographics and Baseline Characteristics ........................................................164 
9.4 
Efficacy Analyses ................................................................................................164 
9.4.1 
Efficacy Endpoints .....................................................................................164 
9.4.2 
Primary Efficacy Analysis .........................................................................164 
9.4.3 
Secondary Efficacy Analyses ....................................................................165 
9.4.3.1 
Progression-free Survival.................................................................165 
9.4.3.2 
Duration of Response .......................................................................165 
9.5 
Safety Analyses ....................................................................................................165 
9.5.1 
Safety Endpoints ........................................................................................166 
9.5.2 
Adverse Events ..........................................................................................166 
9.5.3 
Clinical Laboratory Evaluations ................................................................167 
9.5.4 
Vital Sign Measurements ...........................................................................167 
9.6 
Pharmacokinetic Analysis ....................................................................................167 
9.7 
Exploratory Analysis ...........................................................................................168 
9.8 
Interim Analysis ...................................................................................................168 
10 ADVERSE EVENT MANAGEMENT .........................................................................168 
10.1 
Definition of an Adverse Event ...........................................................................168 
10.2 
Definition of a Serious Adverse Event ................................................................169 
10.3 
Definition of Adverse Events of Special Interest ................................................169 
10.4 
Events or Outcomes Not Qualifying as Serious Adverse Events ........................170 


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10.5 
Clinical Laboratory Assessments as Adverse Events and Serious Adverse 
Events ...................................................................................................................170 
10.6 
Pregnancy or Drug Exposure during Pregnancy ..................................................171 
10.7 
Recording of Adverse Events, Serious Adverse Events, and Adverse Events of 
Special Interest .....................................................................................................171 
10.7.1 
Onset Data of Adverse Events ...................................................................172 
10.7.2 
Resolution Date of Adverse Events ...........................................................172 
10.7.3 
Intensity of Adverse Events .......................................................................172 
10.7.4 
Causal Relationship of Adverse Events to Study Drug .............................172 
10.7.5 
Outcome and Action Taken .......................................................................173 
10.8 
Follow-Up of Adverse Events, Serious Adverse Events, and Adverse Events 
of Special Interest ................................................................................................174 
10.9 
Potential Drug-Induced Liver Injury ...................................................................174 
10.10 Regulatory Aspects of Serious Adverse Event and Adverse Events of Special 
Interest Reporting.................................................................................................174 
11 STUDY ADMINISTRATION.......................................................................................175 
11.1 
Regulatory and Ethical Considerations ................................................................175 
11.1.1 
Regulatory Authority Approvals................................................................176 
11.1.2 
Institutional Review Board or Independent Ethics Committee Approval .176 
11.2 
Patient Information and Consent .........................................................................177 
11.3 
Patient Confidentiality .........................................................................................177 
11.4 
Study Monitoring .................................................................................................178 
11.5 
Case Report Forms and Study Data .....................................................................179 
11.6 
Study Termination and Site Closure ....................................................................179 
11.7 
Modification of the Study Protocol......................................................................180 
11.8 
Retention of Study Documents ............................................................................180 
11.9 
Quality Control and Assurance ............................................................................181 
11.9.1 
Changes to the Protocol and Deviations ....................................................181 
11.9.2 
Study Site Training and Ongoing Monitoring ...........................................181 
11.9.3 
Direct Access to Source Data/ Documents for Audits and Inspections .....182 
11.10 Clinical Study Report ...........................................................................................182 
11.11 Publication and Disclosure Policy .......................................................................182 
11.12 Investigator Oversight ..........................................................................................183 
12 REFERENCE LIST .......................................................................................................184 
13 APPENDICES ...............................................................................................................191 
 


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LIST OF IN-TEXT TABLES 
Table 3-1. 
General Dose Escalation Based on Dose-limiting Toxicities ................41 
Table 5-1. 
Description of Rucaparib Tablets ...........................................................46 
Table 7-1. 
Laboratory Tests - All Treatment Arms .................................................53 
Table 8.A-1 
Description of Lucitanib ........................................................................72 
Table 8.A-2 
Rucaparib and Lucitanib Dose Modification Criteria and Action 
Taken 
74 
Table 8.A-3 
Rucaparib and Lucitanib Dose Reductions ............................................77 
Table 8.A-4  
NCI CTCAE Grading Scale for Hypertension .......................................79 
Table 8.A-5  
NCI CTCAE Grading Scale for Proteinuria ...........................................82 
Table 8.A-6  
Management of Lucitanib-related Proteinuria .......................................83 
Table 8.A-7 
Schedule of Assessments for All Patients in Treatment Arm A 
(Phase 1b and Phase 2) ................................................................................................86 
Table 8.A-8 
Pharmacokinetic Sample Collections in Treatment Arm A (Phase 1b 
and Phase 2) 89 
Table 8.B-1 
Description of Sacituzumab Govitecan ................................................109 
Table 8.B-2 
Sacituzumab Govitecan Preparation for 10 mg/kg Dosing (Assume 
70-kg Patient) .............................................................................................................110 
Table 8.B-3 
Infusion Rate Guidelines for Patients Remaining Stable in Absence 
of Hypersensitivity or Infusion-related Events ..........................................................111 
Table 8.B-4 
Dose Modification and Retreatment Criteria for Rucaparib and 
Sacituzumab Govitecan .............................................................................................113 
Table 8.B-5 
Rucaparib and Sacituzumab Govitecan Dose Reductions ...................117 
Table 8.B-6 
Schedule of Assessments for All Patients in Treatment Arm B 
(Phase 1b and Phase 2) ..............................................................................................123 
Table 8.B-7 
Pharmacokinetic and Immunogenicity Sample Collections in 
Treatment Arm B (Phases 1b and 2) ..........................................................................126 
Table 8.C-1  
Description of M4344 ..........................................................................146 
Table 8.C-2 
Dose Modification and Retreatment Criteria for Rucaparib and 
M4344 
148 
Table 8.C-3 
Rucaparib and M4344 Dose Reductions ..............................................152 
Table 8.C-4 
Schedule of Assessments for All Patients in Treatment Arm C 
(Phase 1b and Phase 2) ..............................................................................................156 
Table 8.C-5 
Pharmacokinetic and Pharmacodynamic Sample Collections in 
Treatment Arm C (Phase 1b and Phase 2) .................................................................159 
Table 10-1. 
Causal Relationship of Adverse Events to Study Drug .......................173 
 


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LIST OF APPENDICES 
Appendix 1 
Cockcroft-Gault Formula .....................................................................191 
Appendix 2 
Example Inhibitors and Inducers of CYP2C8 and CYP3A4 (not an 
inclusive list) 192 
 


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LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS  
Abbreviations 
AAG 
α1-acid glycoprotein 
ACE 
angiotensin converting enzyme 
ADA 
anti-drug antibody 
ADC 
antibody-drug conjugates 
ADCC 
antibody-dependent cytotoxicity 
ADP 
adenosine diphosphate 
ADR 
adverse drug reactions 
AE 
adverse event 
AESI 
adverse event of special interest 
AIDS 
acquired immunodeficiency syndrome 
ALCOA-C 
attributable, legible, contemporaneous, original, accurate, complete 
ALP 
alkaline phosphatase 
ALT 
alanine aminotransferase 
AML 
acute myeloid leukemia 
ANC 
absolute neutrophil count 
AST 
aspartate aminotransferase 
ATM 
ataxia telangiectasia mutated 
ATR 
ataxia telangiectasia mutated and Rad3-related 
AUC 
area under the curve 
AUC0-24h 
area under the curve from time 0 to 24 hours 
AUC0-inf 
area under the curve from time 0 to infinity 
AUC0-last 
area under the curve from time 0 to the last observation 
BCRP 
breast cancer resistance protein 
BER 
base excision repair 
BICR 
blinded independent central review 
BID 
twice a day 
BIW 
twice a week 
BP 
blood pressure 
BRCA 
breast cancer gene 
BRCA1 
breast cancer gene 1 
BRCA2 
breast cancer gene 2 
BRCA1/2 
breast cancer gene 1 or breast cancer gene 2 
BRCAmut 
deleterious mutations within BRCA 
BRCAwt 
BRCA wild-type 
BRCAwt/unk 
BRCA wild-type unknown 


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BUN 
blood urea nitrogen 
CA-125 
cancer antigen-125 
CDC 
complement-mediated cytotoxicity 
CBR 
clinical benefit rate 
CDP 
clinical development program 
CFR 
Code of Federal Regulations 
CHK1 
checkpoint kinase 1 
CI 
confidence interval 
CINV 
chemotherapy-induced nausea and vomiting 
CL/F 
apparent clearance 
CLIA 
Clinical Laboratory Improvement Amendments 
Cmax 
maximum concentration 
Cmin 
minimum concentrations 
CNS 
central nervous system 
CO2/HCO3- 
bicarbonate 
CR 
complete response  
CRO 
contract research organization 
CSR 
clinical study report 
CT 
computed tomography 
ctDNA 
circulating cell-free tumor DNA 
CTCAE 
Common Terminology Criteria for Adverse Events 
CYP 
cytochrome P450 
DBP 
diastolic blood pressure 
DDI 
drug-drug interaction 
DILI 
drug-induced liver injury 
DLT 
dose-limiting toxicity 
DNA 
deoxyribonucleic acid 
DOR 
duration of response 
DSB 
double-strand break 
DVT 
deep venous thrombosis 
EC 
European Commission 
ECG 
electrocardiogram 
ECHO 
echocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
eCRF 
electronic Case Report Form 
EDC 
electronic data capture 
eGFR 
estimated glomerular filtration rate 


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EMA 
European Medicines Agency 
EOC 
epithelial ovarian cancer 
EOI 
end of infusion 
EOT 
end of treatment 
ESMO 
European Society of Medical Oncology 
EU 
European Union 
EudraCT 
European Clinical Trials Database 
FDA 
Food and Drug Administration 
FGF 
fibroblast growth factor 
FGFR 
fibroblast growth factor receptor 
FFPE 
formalin-fixed paraffin-embedded 
FIH 
first-in-human 
FISH 
fluorescence in situ hybridization 
FMI 
Foundation Medicine Inc. 
FSH 
follicle-stimulating hormone 
FU 
follow-up visit 
FTC 
fallopian tube cancer 
gBRCA 
germline BRCA 
gBRCAwt 
germline BRCA wild type 
GCIG 
Gynecologic Cancer InterGroup 
GCP 
Good Clinical Practice 
GCSF 
Granulocyte colony-stimulating factor 
GDPR 
General Data Protection Regulation 
GFR 
glomerular filtration rate 
GLP 
Good Laboratory Practice 
H0 
null hypothesis 
H1 
alternative hypothesis 
H&E 
hematoxylin and eosin 
HED 
human equivalent dose 
HER2 
human epidermal growth factor receptor 2 
HDPE 
high-density polyethylene 
HGOC 
high-grade ovarian cancer 
HGSOC 
high-grade serous ovarian cancer 
HIPAA 
Health Information Portability and Accountability Act 
HIV 
human immunodeficiency virus 
HL 
Hodgkin lymphoma 
HNSTD 
highest non-severely toxic dose 


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HR 
hazard ratio 
HRD 
homologous recombination deficiency 
HRR 
homologous recombination repair 
IB 
Investigator’s Brochure 
IC50 
concentration of inhibitor required for 50% inhibition 
ICF 
Informed Consent Form 
ICH 
International Council for Harmonisation 
ICJME 
International Committee of Medical Journal Editors 
IEC 
Independent Ethics Committee 
IHC 
immunohistochemistry 
IND 
Investigational New Drug 
INN 
International Nonproprietary Name 
INR 
international normalized ratio 
IRB 
Institutional Review Board  
IRT 
interactive response technology 
ITT 
intent-to-treat 
IUD 
intrauterine device 
IUS 
intrauterine system 
IV 
intravenous 
LDH 
lactate dehydrogenase 
LFT 
liver function test 
LOH 
loss of heterozygosity 
LVEF 
Left ventricular ejection fraction 
MATE 
multidrug and toxin extrusion 
mCRPC 
metastatic castration-resistant prostate cancer 
MCH 
mean corpuscular hemoglobin 
MCHC 
mean corpuscular hemoglobin concentration 
MCV 
mean corpuscular volume 
MDCK 
Madin-Darby Canine Kidney (cell line) 
MDS 
myelodysplastic syndrome 
MedDRA 
Medical Dictionary for Regulatory Activities 
MMAE 
monomethyl auristatin E 
MMR 
mismatch repair 
MRI 
magnetic resonance imaging 
mRNA 
messenger ribonucleic acid 
MTD 
maximum tolerated dose 
MUGA 
multiple-gated acquisition 


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NCI 
National Cancer Institute 
NGS 
next-generation sequencing 
NOAEL 
No-Observed-Adverse-Effect-Level 
NSCLC 
non-small cell lung cancer 
NTCP 
sodium/taurocholate cotransporting polypeptide 
OAT 
organic anion transporter 
OATP 
organic anion transporting polypeptide 
OC 
ovarian cancer 
OCT 
organic cation transporter 
ORR 
overall response rate 
OS 
overall survival 
PARP 
poly (adenosine diphosphate [ADP]-ribose) polymerase 
PD 
progressive disease 
PDGF 
platelet derived growth factor 
PDGFR 
platelet-derived growth factor receptors 
PDX 
patient-derived xenograft 
PE 
pulmonary embolism 
PET 
positron emission tomography 
PFI 
platinum-free interval 
PFS 
progression-free survival 
P-gp 
P-glycoprotein 
PIS 
patient information sheet 
PK 
pharmacokinetic 
PPC 
primary peritoneal cancer 
PPI 
proton pump inhibitors 
PPK 
population pharmacokinetics 
PR 
partial response 
PRES 
Posterior Reversible Encephalopathy Syndrome 
QD 
once a day 
QTcF 
QT interval corrected using Fridericia's method 
RBC 
red blood cell 
RECIST 
Response Evaluation Criteria in Solid Tumors 
RP2D 
recommended Phase 2 dose 
RS 
replication stress 
SAE 
serious adverse event 
sALCL 
systemic anaplastic large cell lymphoma 
SAP 
statistical analysis plan 


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SAR 
serious adverse drug reaction 
SAS 
statistical analysis software 
SBP 
systolic blood pressure 
SCLC 
small cell lung cancer 
SD 
stable disease 
StD 
standard deviation 
SI 
International System of Units 
SN-38 
active metabolite of irinotecan 
STD 
severely toxic dose 
STD10 
severely toxic dose to 10% of the population 
SmPC 
Summary of Product Characteristics 
SOC 
system organ class 
SOP 
standard operating procedure 
SUSAR 
suspected unexpected serious adverse reaction 
t1/2 
elimination half-life 
T3 
triiodothyronine 
T4 
thyroxine 
tBRCA 
tumor tissue deleterious alteration in BRCA 1 or BRCA 2 
T-DM1 
trastuzumab emtansine 
TEAE 
treatment-emergent adverse event 
Topo1 
topoisomerase 1 
TMA 
thrombotic microangiopathy 
tmax 
maximum concentration 
TNBC 
triple-negative breast cancer 
Trop-2 
trophoblast cell-surface antigen 
TSH 
thyroid stimulating hormone 
UC 
urothelial cancer 
UGT 
uridine diphosphate glucuronosyltransferase 
ULN 
upper limit of normal 
US 
United States 
VEGF 
vascular endothelial growth factor 
VEGFR 
vascular endothelial growth factor receptor 
V/F 
apparent volume of distribution 
Vss 
volume of distribution at steady-state 
Vss/F 
apparent volume of distribution at steady state 
Vz/F 
Apparent volume of distribution during terminal phase after oral 
administration 
WBC 
white blood cell 


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WOCBP 
women of child bearing potential 
WT 
wild type 
 


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1 
INTRODUCTION 
1.1 
Background 
Poly (adenosine diphosphate [ADP]-ribose) polymerase (PARP) enzymes play a critical role 
in base excision repair (BER).1 When PARP function is impaired, double-stranded 
deoxyribonucleic acid (DNA) breaks accumulate in the absence of effective BER; in 
homologous recombination deficient (HRD) cells, these breaks cannot be accurately repaired, 
resulting in synthetic lethality and cell death.2 While mutated breast cancer gene 1 (BRCA1) 
and BRCA2 genes are most commonly associated with HRD, mutations or functional 
inactivation of other essential homologous recombination repair (HRR) proteins can also 
cause HRD. In addition, over the past decade, it has been determined that patterns of 
genomic loss of heterozygosity (LOH), a phenotypic marker of HRD, has been shown to be a 
biomarker of PARP sensitivity.13 
The development of PARP inhibitors has advanced steadily over the last few years. There are 
currently 4 PARP inhibitors marketed in the United States (US), with various clinical 
indications in ovarian and breast cancer.3,14,15 While the single-agent activity of many PARP 
inhibitors has been established in HRD ovarian tumors, the utility of PARP inhibitors in the 
treatment of patients with HRR-proficient ovarian cancer is less certain given that these 
tumors generally do not respond as well to monotherapy PARP inhibitor treatment. 
Combining a PARP inhibitor with agents that inhibit HRR or may induce HRD may 
represent an effective strategy to sensitize HRR-proficient tumors to PARP inhibitor 
treatment.16 Further, in vivo/in vitro data evaluating the synergistic antitumor activity of 
PARP inhibitors with select targeted agents support several combination strategies.  
1.1.1 
Rucaparib 
Rucaparib is a potent, oral small molecule inhibitor of PARP enzymes, including PARP-1, 
PARP-2, and PARP-3, that play a critical role in BER.1  
Rucaparib (Rubraca®) is approved in the US for the treatment of adult patients with 
deleterious BRCA mutation (germline and/or somatic)-associated epithelial ovarian (EOC), 
fallopian tube (FTC), or primary peritoneal (PPC) cancer who have been treated with 2 or 
more prior chemotherapies, and for the maintenance treatment of adult patients with 
recurrent EOC, FTC, or PPC who are in a complete or partial response to platinum-based 
chemotherapy.3 Rucaparib is also 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.4 In addition, rucaparib is being developed for the treatment of 
cancer associated with HRD, defined by the presence of a deleterious mutation in BRCA1, 
BRCA2, or other HRR genes, and/or high percentage of tumor genome with LOH, which is a 
phenotypic consequence of HRD. 
A brief overview of data from nonclinical and clinical studies are provided below and 
described in detail in the rucaparib Investigator’s Brochure (IB).  


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1.1.1.1 
Nonclinical Experience 
The results from nonclinical studies are consistent with the mechanism of action and 
pharmacological effects of PARP inhibition.  
Pharmacological assessment demonstrated that rucaparib is a potent and selective inhibitor of 
PARP-1, PARP-2, and PARP-3 and has robust and durable in vitro and in vivo activity in 
multiple BRCA1/2 mutant cell lines and xenograft models. Rucaparib was also active in a 
BRCA wild-type models, consistent with in vitro data suggesting that rucaparib is active in 
cells with other defects in HRR through synthetic lethality. In vitro screens suggested that 
rucaparib has a limited potential for off-target effects.  
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 resistant 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. Rucaparib reversibly inhibited CYP1A2, CYP2C9, CYP2C19, and CYP3A, and to 
a lesser extent CYP2C8, CYP2D6, and UDP-glucuronosyltransferase 1A1 (UGT1A1). 
Rucaparib induced CYP1A2, and down-regulated CYP2B6 and CYP3A4 in human 
hepatocytes at clinically relevant exposures. Rucaparib is a potent inhibitor of multidrug and 
toxin extrusion 1 (MATE1) and MATE2-K, a moderate inhibitor of organic cationic 
transporter 1 (OCT1) and may inhibit P-gp and BCRP in the gut. 
Oral dosing of rucaparib in single and repeat dose toxicity studies in rats and dogs resulted in 
toxicity to the hematopoietic, lymphopoietic, and gastrointestinal systems. These toxicities 
were generally both reversible upon recovery and predictive of toxicities observed in 
patients. Rucaparib was shown to be clastogenic in an in vitro chromosomal aberration assay 
suggesting potential genotoxicity in humans. Reproductive and development toxicity studies 
in rat showed that rucaparib caused maternal toxicity and was 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.17-20 
1.1.1.2 
Clinical Experience 
Rucaparib is being evaluated in Phase 1, 2, and 3 clinical studies in patients with advanced 
cancer with and without evidence of HRD. Rucaparib clinical studies have evaluated (and 
continue to evaluate) patients with relapsed, high-grade ovarian, fallopian tube, or primary 
peritoneal cancer in both the treatment and maintenance settings.  
Rucaparib is being evaluated as treatment for patients with metastatic castration-resistant 
prostate cancer (mCRPC), both as monotherapy and in combination with nivolumab. 
Clinical pharmacology studies in patients with advanced solid tumors have evaluated 
rucaparib drug-drug interactions (DDIs) and mass balance and drug metabolism. Additional 


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clinical pharmacology studies continue to characterize rucaparib DDIs, as well as rucaparib 
PK in special populations. 
Additional studies of rucaparib as monotherapy and in combination with other anticancer 
therapies are planned in ovarian, prostate, and bladder cancers, as well as other tumors. 
1.1.1.2.1 
OVERVIEW OF PHARMACOKINETICS AND DRUG-DRUG INTERACTIONS 
Assessment of rucaparib PK in cancer patients showed an approximate dose proportional 
exposure after once a day (QD) or twice a day (BID) dosing, rapid absorption with Cmax 
achieved within 1.5 to 6 hours. The oral bioavailability was 36% and elimination half-life 
(t1/2) was approximately 24 hours. Rucaparib was moderately bound to human plasma 
proteins in vitro (70%).  
At a dose of 600 mg BID rucaparib, steady state was achieved after approximately 1 week 
with approximately 4-fold accumulation. A high-fat meal increased the Cmax and area under 
the curve (AUC)0-24h of rucaparib by 20% and 38%, respectively, as compared with that 
under fasted conditions. The effect of food on rucaparib PK is not considered to be clinically 
significant, thus rucaparib can be taken with or without food. 
In vitro, rucaparib showed slow enzymatic turnover in human liver microsomes and 
hepatocytes. Recombinant CYP2D6, and to a lesser extent CYP1A2 and CYP3A4, were able 
to metabolize rucaparib. In cancer patients, M324, a carboxylic acid, was a major inactive 
metabolite of rucaparib. 
Drug interactions with rucaparib as a substrate were assessed in a population PK (PPK) 
analysis. CYP2D6 phenotypes (poor metabolizers, intermediate metabolizers, normal 
metabolizers, and ultrarapid metabolizers) and CYP1A2 phenotypes (normal metabolizers 
and hyper-inducers) did not significantly impact the steady-state exposure of rucaparib at 
600 mg BID. Concomitant administration of strong CYP1A2 or CYP2D6 inhibitors did not 
significantly impact rucaparib PK. Current smokers had overlapping rucaparib exposures as 
compared to nonsmokers and former smokers. Collectively, the results suggest that CYP1A2 
and CYP2D6 play limited role in rucaparib metabolism. Although in vitro rucaparib 
metabolism mediated by CYP3A4 was slow, a significant contribution of CYP3A4 in vivo 
cannot be excluded. No rucaparib dose adjustment is recommended when concomitantly 
administered with CYP inhibitors or inducers. 
Concomitant treatment with proton pump inhibitors (PPIs) showed no clinically significant 
effect on rucaparib PK. No dose modification of rucaparib is required for patients who are 
receiving concomitant treatment with a PPI. 
Results from Study CO-338-044 evaluating potential 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 the PK of oral digoxin 
(a P-gp substrate). Caution should be exercised in the concomitant use of drugs that are 
sensitive clinical substrates of the above CYP enzymes (refer to the rucaparib IB, 
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1.1.1.2.2 
OVERVIEW OF EFFICACY 
Rucaparib was originally approved by the US Food and Drug Administration (FDA) in 
December 2016 as monotherapy treatment of patients with deleterious BRCA mutation 
(germline and/or somatic) associated advanced ovarian cancer who have been treated with ≥ 
2 chemotherapies. As of May 2018, rucaparib was approved by the European Commission 
for the same indication with the exception that patients must be intolerant to subsequent 
platinum-based chemotherapy.4 The recommended dose of rucaparib is 600 mg BID.  
The primary outcome measure on which approval by FDA for the treatment indication was 
based is investigator-assessed overall response rate (ORR) per Response Evaluation Criteria 
in Solid Tumors Version 1.1 (RECIST v1.1), with ORR by central independent radiological 
review conducted as a supportive analysis. ORR by investigator was 53.8%, while ORR by 
independent review was 41.5%, confirming the results of investigator assessment for this 
endpoint.21 Responses were durable, indicated by a duration of response (DOR) by 
investigator assessment of approximately 9.2 months.  
In April 2018, rucaparib was approved by the US FDA for the maintenance treatment of 
adult patients with recurrent EOC, FTC, or PPC who are in a complete or partial response to 
platinum-based chemotherapy.3 This approval was based on Study CO-338-014 (ARIEL3), a 
randomized, placebo-controlled Phase 3 study. In this study, investigator-assessed 
progression-free survival (invPFS) was the primary efficacy endpoint, with PFS by blinded 
independent central review (bicrPFS) conducted as a key, stand-alone, secondary endpoint. 
Overall, rucaparib as maintenance treatment reduced the risk of progression or death by 
63.5% (hazard ratio [HR] 0.365 [95% confidence interval (CI), 0.295-0.451]; p < 0.0001) in 
the intent-to-treat (ITT) population, demonstrating a strong treatment effect over placebo. 
Analysis of non-nested, non-overlapping patient subpopulations indicate that the significant 
improvement in PFS observed in the ITT population was not driven only by the tBRCA 
subpopulation (tumor tissue deleterious alteration in BRCA1 or BRCA2) or HRD 
subpopulation (tBRCA as well as tumors that were non-tBRCA, but with genomic LOH 
≥16%). Nearly half (44.6%) of the ITT patients in the rucaparib group showed benefit at 1 
year compared to 8.8% in the placebo group.22 At 18 and 24 months, 32.0% and 26.0%, 
respectively, of patients who received rucaparib were still progression-free compared to 5.8% 
and 2.6% in the placebo group, respectively. These investigator-assessed results were 
confirmed by results of BICR. 
1.1.1.2.3 
OVERVIEW OF SAFETY 
Results of a recent integrated safety analysis in over 1,000 patients with ovarian or prostate 
cancer who received 600 mg BID rucaparib in the treatment or maintenance setting showed 
that the most common treatment-emergent adverse events (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, alanine aminotransferase (ALT)/ aspartate aminotransferase (AST) increased, 
decreased appetite, and dysgeusia. The most common TEAE ≥ Grade 3 include 
anemia/decreased hemoglobin, ALT/AST increased, neutropenia/decreased absolute 
neutrophil count (ANC), and asthenia/fatigue. Section 6.6 of the rucaparib Investigator’s 


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Brochure (IB) serves as guidance to the investigator on adverse drug reactions (ADRs) for 
rucaparib, based on incidence of TEAEs by all CTCAE grades and by ≥ Grade 3. 
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 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),23,24  and few patients 
discontinued rucaparib due to ALT/AST elevations.22,25 Similarly, elevations in creatinine 
were self-limiting and generally stabilized over time. The majority of creatinine elevations 
were Grade 1 or Grade 2. 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 (Section 1.1.1.1). 
An updated analyses of safety presented in the US prescribing information3 and the EU 
Summary of Product Characteristics (SmPC)4 demonstrate that safety results in ovarian 
cancer patients treated with rucaparib have remained consistent with those previously 
reported, and that the safety profile across both the treatment and maintenance indications is 
consistent.  
Effects on cardiac channel activity in vitro and a comprehensive assessment of the effects of 
rucaparib on electrocardiogram (ECG) parameters in cancer patients demonstrated a low risk 
of cardiac effects by rucaparib. 
Myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML) are considered 
adverse events of special interest (AESI), 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. Based on 
these confounding factors, there is insufficient scientific evidence to conclude that MDS and 
AML are causally related to rucaparib.  
More recently, pneumonitis was classified as an AESI. TEAEs 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. Clovis is seeking to better understand whether or not there is 
a relationship between pneumonitis and rucaparib treatment, hence the AESI designation in 
order to gather the necessary information to enable a thorough evaluation and assessment. 


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Pneumonitis and similar events (interstitial lung disease, pulmonary fibrosis, acute interstitial 
pneumonitis, alveolitis necrotizing, alveolitis, hypersensitivity pneumonitis, and organizing 
pneumonia) will be considered an AESI if occurring on treatment or within 28 days after last 
dose of study drug(s). More information on AESIs is provided in the rucaparib IB. 
1.2 
Rationale for the Study 
PARP inhibitors have been explored in combination with chemotherapy; however, such 
combinations were challenging to administer due to overlapping toxicity, specifically 
myelosuppression, therefore novel combination approaches with more selective targeted 
agents are currently thought to have more potential. Combination therapy with a PARP 
inhibitor would aim to increase accumulation of DNA damage and subsequent dependence 
on HRR, such as in the combination of PARP inhibitor with a DNA-damaging 
chemotherapy, radiation, or targeted therapies that induce HRD. Agents that inhibit 
topoisomerase 1, including irinotecan and topotecan, have demonstrated synergy with PARP 
inhibitors in a variety of human tumor cell lines, including ovarian and breast cancers.5,6 The 
PARP inhibitor olaparib has been shown to potentiate the cytotoxicity of SN-38, the active 
metabolite in irinotecan and topotecan, irrespective of mismatch repair (MMR) status in a 
panel of MMR-deficient or MMR-efficient cancer cell lines.7 A clinical study of the PARP 
inhibitor veliparib combined with topotecan showed a mechanistic interaction between the 2 
drugs, resulting in delayed repair of Topo1-mediated DNA damage, despite there being some 
challenges with overlapping hematologic toxicities.8 Targeted delivery of SN-38 to cancer 
cells through administration of an antibody-drug conjugate (ADC) has greater potential for 
combination therapy with a PARP inhibitor by reducing off-target and additive toxicity. 
Other combinations would aim to induce a BRCA-like phenotype in order to elicit PARP 
inhibitor and BRCA-like synthetic lethality, as has been shown to occur in combinations 
between PARP inhibitors angiogenesis inhibitors (such as vascular endothelial growth factor 
[VEGF] inhibitors) and ataxia telangiectasia mutated and Rad3-related (ATR) inhibitors. The 
combination of a PARP inhibitor with a VEGF inhibitor, which have distinctly different 
mechanisms of action, has also demonstrated synergistic effects in nonclinical studies (Clovis 
Oncology, data on file). In addition, a Phase 2 clinical study in patients with recurrent 
ovarian cancer treated with the PARP inhibitor, olaparib, and an anti-angiogenic agent, 
cediranib, has shown promise.9 Nonclinical data indicate that ATR inhibition increases 
sensitivity to PARP inhibition10 and that defects in ATR signaling may result in synthetic 
lethality with PARP inhibition.11 Inhibition of ATR may be a mechanism to overcome 
primary and acquired resistance to PARP inhibition. 
This study aims to evaluate the PARP inhibitor, rucaparib, in combination with various 
agents that have shown promise as an antitumor agent through different mechanisms of 
action. The rucaparib combinations selected for evaluation within this study were carefully 
chosen based on nonclinical and clinical data, and theoretical concepts to support a potential 
efficacious synergism. The rationales for each rucaparib combination are provided in 
Section 8.X.3 of each respective treatment arm. 
 


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2 
STUDY OBJECTIVES 
2.1 
Primary Objective  
The primary objectives of this study are as follows: 
Phase 1b of each Treatment Arm 
• To evaluate the safety and tolerability of rucaparib in combination with a second 
anticancer agent and to determine the maximum tolerated dose (MTD) and/or the 
recommended Phase 2 dose (RP2D) of the combination. 
 
Phase 2 of each Treatment Arm 
• To evaluate the efficacy of rucaparib in combination with a second anticancer agent by 
measuring investigator-assessed confirmed best overall response rate (ORR) by 
RECIST v1.1 in one or more expansion cohorts evaluating the combination. 
 
2.2 
Secondary Objectives  
The secondary objectives of this study are as follows: 
Phase 1b of each Treatment Arm 
• To characterize the PK of rucaparib (Treatment Arm A and Treatment Arm C) and the 
second anticancer agent (all treatment arms), as well as the metabolites for the second 
anticancer agent (Treatment Arm B) when rucaparib and the second anticancer agent are 
co-administered. 
• To evaluate the preliminary efficacy of rucaparib in combination with a second 
anticancer agent in various solid tumors.  
 
Phase 2 of each Treatment Arm 
• To evaluate the safety and tolerability of rucaparib in combination with a second 
anticancer agent. 
• To evaluate progression-free survival (PFS) in one or more expansion cohorts evaluating 
the combination.  
• To evaluate duration of response (DOR) in one or more expansion cohorts. 
 


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2.3 
Exploratory Objectives 
Exploratory objectives in both parts of this study are as follows:  
• To assess tumor tissue biomarkers that correlate with response to the combination. 
• To evaluate circulating cell-free tumor DNA (ctDNA) as a molecular marker of response 
to the combination. 
• To evaluate biomarkers associated with resistance to the combination. 
• To assess genomic changes over time in plasma and tumor samples. 
• To determine steady-state exposure of rucaparib and the second anticancer agent (all 
treatment arms) by sparse PK sampling. 
• To evaluate the development of anti-drug antibodies (ADAs) (Treatment Arm B).  
• To characterize the PK of metabolites of the second anticancer agent (Treatment Arm C) 
when rucaparib and the second anticancer agent are co-administered. 
 
 


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3 
STUDY DESIGN 
3.1 
Overall Study Design and Plan 
This is a Phase 1b/2, open-label, study with multiple treatment arms evaluating the safety, 
tolerability, PK, and preliminary efficacy of rucaparib in combination a second anticancer 
therapy in patients with an advanced/metastatic solid malignancy (Phase 1b), followed by 
evaluation of the combination in one or more specific patient populations in an expansion 
phase (Phase 2 cohorts). 
• Phase 1b/ Dose-escalation Phase: This portion of the study will enroll patients with 
advanced malignancy who have relapsed following prior treatment or are not eligible for 
standard of care treatment. Dose escalation will follow a 3+3 design. Patients will receive 
rucaparib in combination with a second targeted anticancer therapy (defined within the 
respective treatment arm section) in order to determine the MTD, if possible, and RP2D 
for the combination. An expanded evaluation of the RP2D may be conducted in up to 10 
additional patients in each combination.  
• Phase 2/ Expansion Phase: In Phase 2, the study drug combination administered at the 
RP2D will be evaluated for efficacy, safety, tolerability, PK, and pharmacodynamics in 
patients as defined for each treatment arm and cohort (within Section 8).  
 
Phase 2 of each treatment arm will not commence until the RP2D has been established in 
Phase 1b. Patients participating in this study will enroll into either Phase 1b or Phase 2, but a 
patient cannot enroll into both phases of the same treatment arm. This section describes the 
general features of the study, common to each treatment arm. The specifics of the study 
design, including schedule of assessments, and patient population with inclusion/ exclusion 
criteria, of each treatment arm are described in Section 8. 
3.1.1 
Screening Phase 
All patients will undergo screening assessments prior to enrollment; the time frame for 
screening assessments is specified under the respective treatment arms.  
Screening assessments will include, but may not be limited to, demographics and medical 
history, prior cancer treatments, prior and current medications and procedures, 12-lead ECG, 
Eastern Cooperative Oncology Group (ECOG) performance status, hematology and 
chemistry, urinalysis, physical examination, vital signs measurements, radiologic assessment 
by CT or magnetic resonance imaging (MRI). Patients will be required to provide archival 
tumor tissue or a more recently obtained tissue sample, as well as blood samples, for 
genomic analysis. Data from procedures that are considered standard of care and performed 
before obtaining patient informed consent for the study may be collected and entered into the 
electronic case report form (eCRF), where allowable. Additional screening procedures may 
be done as appropriate for a particular combination, the details of which can be found in the 
schedule of assessments table for each treatment arm. 


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3.1.2 
Enrollment 
For Phase 1b, including dose escalation and any RP2D expansion, eligible patients will be 
enrolled in parallel into open dose-escalation cohorts across the treatment arms. If a patient 
appears to be eligible for more than one treatment arm that is open to enrollment, the 
investigator will be responsible for selecting the most appropriate treatment arm for the 
patient. A limited number of sites (3-6) will enroll patients in the Phase 1b portion of the 
study. Once the RP2D of the combination has been provisionally established, up to 10 
additional patients may be enrolled at the RP2D and treated as part of Phase 1b to further 
characterize safety, tolerability, efficacy, and PK and confirm that this is the optimal dose 
combination to evaluate in Phase 2. 
Enrollment in the Phase 2 portion for all treatment arms will be competitive. Sites may be 
actively enrolling in more than 1 treatment arm simultaneously. Sites participating in 
Phase 1b activities may also enroll patients in Phase 2. 
3.1.3 
Treatment Phase 
Treatment cycles will be 21 or 28 days in length, depending upon the study drug 
combination; cycles are defined within each specific treatment arm (Section 8.X.4). 
All patients will be monitored for safety throughout the treatment phase. Assessments will 
include, but may not be limited to, physical examination, vital signs and weight 
measurement, hematology, chemistry, concomitant medications, ECOG performance status, 
disease status assessment, 12-lead ECG, adverse events (AEs) with any associated therapies 
and procedures, study drug administration and accountability. Urinalysis will be performed 
as clinically indicated, except where otherwise noted in the schedule of assessments for each 
treatment arm. Blood samples will also be collected for PK, biomarker, and immunogenicity 
analyses, as applicable. 
All patients will be assessed for disease status by RECIST v1.1 per the time interval specified 
within each treatment arm in Section 8 (flexibility with scheduling within 1 week prior to 
planned imaging date is permitted) until 1 of the following occurs: 
• radiological disease progression as assessed by the investigator,  
• death,  
• loss to follow-up,  
• withdrawal from study,  
• study termination, or  
• initiation of subsequent anticancer treatments.  
 
All responses (complete response [CR] or partial response [PR]) must be confirmed with a 
scan no less than 4 weeks after the initial response.  


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Disease progression will be determined by RECIST v1.1 (Section 7.3.1). If the radiologic 
assessment does not confirm disease progression, patients should continue on treatment and 
be assessed by RECIST v1.1 per the treatment arm schedule of assessments. Patients 
experiencing disease progression by RECIST v1.1, as assessed by the investigator, will be 
discontinued from study treatment and enter into follow-up. However, if the patient has met 
criteria for radiologic progression by RECIST, but the patient is still receiving benefit from 
the study drug(s) (eg, patient has mixed radiologic response or is continuing to have 
symptomatic benefit), according to the investigator, then continuation of treatment will be 
considered upon discussion with the medical monitor (see Section 5.9).  
3.1.3.1 
Phase 1b 
In the Phase 1b portion of each treatment arm, there will be an estimated 6 to 12 
dose-escalation cohorts, with a minimum of 3 patients enrolled in each cohort, followed by an 
expanded evaluation of the RP2D in up to 10 additional patients. 
Dose escalation will follow a 3+3 design (Table 3-1). Rucaparib will be administered BID 
continuously up to a maximum of 600 mg BID, and the second study drug will be 
administered as specified within each respective treatment arm in Section 8. The starting 
doses and escalation plan for each combination treatment is specified in Section 8.X.4.2.1. 
Dose-limiting toxicities (DLTs) are defined according to criteria specified for each 
combination treatment and assessed by the investigator, based on toxicity grade (according to 
the National Cancer Institute Common Terminology Criteria for Adverse Events [NCI 
CTCAE] v5.0), clinical significance, and possible relationship to either study drug. DLTs are 
defined for each combination treatment within Section 8.X.4.2.1.1. The MTD for the study 
drug combination is defined as the maximum dose combination at which < 33% of patients 
experience a DLT during Cycle 1 (the DLT-evaluation period). If a DLT is observed in 1 of 
3 patients, then 3 additional patients will be enrolled at that same dose level (Table 3-1). 
Dose escalation will continue until at least 2 of the 3 to 6 patients treated at a dose level 
experience a DLT or until the maximum dose to be evaluated is reached, whichever occurs 
first. If the end of dose escalation is reached due to DLTs, the next lower dose will then be 
considered the MTD. Alternatively, if the different between the MTD and the maximally 
delivered dose is significant (such as 100%), then a more modestly de-escalated dose may be 
explored (eg, 20% to 50%). 
Prior to initiating treatment at each new combined dose level or prior to expanding an 
existing dose level, a safety teleconference will be held to review patient data, including but 
not limited to demographics, PK results (if available), study drug combination dosing, 
concomitant medications, hematology and chemistry, and AEs, and then confer and 
document agreement that dose escalation and/or expanding an existing dose level is/are 
considered appropriately safe. Safety teleconferences will include study investigators, the 
sponsor’s medical monitor, and may include other representatives or designees of the sponsor 
and the study sites. 


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If a patient is not evaluable for MTD within the DLT-evaluation period for reasons other than 
treatment-related toxicities, an additional patient may be enrolled at the same dose level. If 
the first dose level exceeds the MTD, other dosing schedules may be explored.  
In order to be included in the DLT-evaluable group, a patient in Phase 1b must have received 
at least 80% of the planned doses of oral study drug(s) (both IV doses for Treatment Arm B) 
or experienced a DLT within the first cycle of combination treatment (Section 9.2). No dose 
reductions will be permitted during the DLT-evaluation period, unless the patient has 
experienced a DLT. 
Table 3-1. 
General Dose Escalation Based on Dose-limiting Toxicities 
Number of Patients with DLT  
at a Given Dose Cohort 
Escalation Decision Rule 
0 of 3 
Enroll 3 patients into next dose cohort 
1 of 3 
Enroll 3 additional patients to this dose cohort. 
If none of these 3 patients experiences a DLT, 
proceed to the next dose cohort. 
If 1 or more experience a DLT, cease dose 
escalation. 
The MTD will be declared.a 
≥ 2 
Stop dose escalation.  
The MTD may be declared.a. 
Abbreviations: DLT = dose-limiting toxicity; MTD = maximum tolerated dose. 
a 
Enrollment to a lower combination dose level may be initiated. 
 
3.1.3.1.1 
DOSE-LIMITING TOXICITY CRITERIA 
A DLT is defined according to criteria specified for each combination treatment and assessed 
by the investigator, based on toxicity grade (according to the NCI CTCAE v5.0), clinical 
significance, and possible relationship to either study drug (refer to Section 10.7.4 for 
consideration of causal relationship).  
The DLT-evaluation period for the determination of dose escalation is the first cycle of 
rucaparib combination treatment (the first 21 or 28 days, depending upon the treatment arm). 
3.1.3.1.2 
RP2D SELECTION AND EXPANSION 
The RP2D for evaluation in the Phase 2 portion will be selected based on overall safety and 
tolerability, PK, as well as any efficacy, if observed. The RP2D may or may not be the same 
as the MTD identified in the dose escalation. For example, if the MTD is not reached, if 
exposure at the MTD is much higher than the level believed to be required for efficacy, or if 
subsequent cycles of treatment provide additional insight on the safety profile, then the RP2D 
may be a different, although not higher, dose than the MTD. 


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Once the RP2D of the combination has been provisionally established, up to 10 additional 
patients may be enrolled at the RP2D and treated as part of Phase 1b, in order to further 
characterize safety, tolerability, and PK and confirm that this is the optimal dose combination 
to evaluate in Phase 2. Since the RP2D may be selected based on evaluation of as few as 
3 patients, there is low certainty that the RP2D has a DLT rate that is < 33%. Enrolling 
additional patients will increase the certainty that the Phase 2 portion of the study is 
evaluated at a dose with a DLT rate < 33%. If the data from this group of patients in the 
RP2D expansion differs significantly from those initially treated at this dose, a different dose 
combination may be evaluated to determine the optimal RP2D. 
3.1.3.1.3 
PHASE 1B  – CYCLE 2 AND BEYOND 
Following the DLT-evaluation period in Phase 1b, patients will be monitored for safety, PK, 
and efficacy as outlined in the Schedule of Assessments and PK Assessments within each 
respective treatment arm section (Section 8.X.8). 
After Cycle 1 (DLT-evaluation period), recommendations for dose modification for the 
management of specific AEs are provided within each respective treatment arm section 
(Section 8.X.6.4). 
Patients tolerating the investigational treatment(s) at the assigned dose combination for at 
least 4 cycles may be permitted to escalate to the next highest combination dose level as long 
as the new dose level is lower than that being currently evaluated for safety and tolerability 
and/or the dose level is the same or lower than that determined to be the RP2D, and only 
after discussion with the study’s medical monitor.   
Patients will be treated until disease progression, unacceptable toxicity, patient or 
investigator request to discontinue, death, initiation of any other cancer therapy, positive 
pregnancy test, or termination of the study (Section 3.2). 
3.1.3.2 
Phase 2 
Enrollment into the Phase 2 portion may begin when the RP2D is established. Patients in the 
Phase 2 portion will be assessed for safety and efficacy at the RP2D.  
Phase 2 will enroll patients into specified cohorts for each treatment combination, and a 
Simon 2-stage design12 will be utilized for each of the planned Phase 2 cohorts. Each cohort 
will be evaluated with the option to stop enrollment in the cohort if the prespecified 
confirmed responses are not observed (described in Section 8.X.9.1).  
The Phase 2 cohorts within each treatment arm are based on nonclinical and clinical data 
provided in Section 8.X.3.2 of each respective treatment arm. 
Patients will be monitored for safety, PK, and efficacy as outlined in the Schedule of 
Assessments and PK Assessments within each respective treatment arm section 
(Section 8.X.8). Recommendations for dose modification for the management of specific 
AEs are provided within each respective treatment arm section (Section 8.X.6.4). Treatment 
will continue until disease progression, unacceptable toxicity, patient or physician request to 


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discontinue, death, initiation of any other cancer therapy, positive pregnancy test, or 
termination of the study (Section 3.2). 
3.1.4 
End of Treatment and Safety Follow-up 
Upon treatment discontinuation, regardless of reason (with the exception of withdrawal of 
consent or death), patients will have an End of Treatment Visit, and assessments are specified 
for each treatment arm in the Schedule of Assessments within Section 8.X.8. 
All patients will be followed for at least 28 days after the last dose of study drug. 
Assessments are specified for each treatment arm in the Schedule of Assessments within 
Section 8.X.8 
Patients who discontinue treatment for a reason other than disease progression or death 
should continue to have tumor scans performed at the interval specified for that treatment 
arm until radiological disease progression as assessed by the investigator, death, loss to 
follow-up, withdrawal from study, study termination, or initiation of subsequent anticancer 
treatments. 
An optional tumor biopsy will be collected from patients who experience disease progression 
and provide appropriate consent. 
3.2 
Removal of Patients from Therapy or Assessment 
A patient must be discontinued from treatment with study drug if any of the following apply: 
• Consent withdrawal at the patient's own request or at the request of their legally 
authorized representative. 
• Progression of patient's underlying disease by RECIST v1.1 as assessed by the 
investigator, unless patient is still receiving benefit from the study drug(s) according to 
the investigator, and the patient has provided additional consent (see Section 5.9). 
• Initiation of any other anticancer therapy. 
• Any event, adverse or otherwise, that, in the opinion of the investigator, would pose an 
unacceptable safety risk to the patient. If it is determined that 1 of the study drugs in the 
combination is posing a safety risk and that study drug is permanently discontinued, 
administration of the other study drug may continue if none of the other withdrawal 
criteria have been met and the investigator believes that the patient may continue to 
receive benefit. 
• Any concomitant illness that, in the opinion of the investigator, would affect assessments 
of the clinical status to a significant degree and requires discontinuation of therapy. 
• A positive pregnancy test at any time during the study. 
 
 


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3.3 
End of Study 
The study will be considered ongoing until all patients have either met one of the withdrawal 
criteria (Section 3.2) or have withdrawn consent for the study, or the sponsor terminates the 
study.  
The sponsor may discontinue the study or an individual treatment combination early for any 
of the reasons noted in Section 11.6.  
4 
OVERALL STUDY POPULATION SELECTION 
Phase 1b of each treatment arm will enroll patients with advanced malignancy who are 
relapsed to or inappropriate for approved, standard treatment. 
Phase 2 will enroll 1 or more specific patient populations defined for each treatment arm 
(Phase 2 expansion cohorts). 
The number of patients estimated to be enrolled into each treatment arm and each Phase 2 
cohort are described in Section 8.X.5 of the respective treatment arms. 
4.1 
All Patients or All Partners of Patients of Reproductive Potential 
Pregnancy is an exclusion criterion. Women of childbearing potential or male patients of 
reproductive potential with female partners of childbearing potential must not be considering 
getting pregnant and must avoid pregnancy during the study and for at least 6 months after 
the last dose of rucaparib or longer if required for the second study drug, or longer if 
requested by local authorities.  
Female patients of childbearing potential must have a negative serum or plasma pregnancy 
test result ≤ 3 days prior to administration of the first dose of study drug. In addition, a serum 
or plasma pregnancy test must be performed ≤ 3 days prior to Day 1 of every cycle during 
the Phase 1b or Phase 2 Treatment Phases and at the time of treatment discontinuation. 
Pregnancy testing will be conducted locally. Treatment should be discontinued immediately 
in any woman found to have a positive pregnancy test while taking study drug. 
Male patients are required to use a condom during sex with a partner to avoid the possibility 
of exposure of the partner to study drug, regardless of whether the partner is a woman of 
childbearing potential or not. Male patients must not make semen donations during treatment 
and for 6 months following the last dose of study drug(s). 
Male patients are considered to be of reproductive potential unless permanently sterile by 
bilateral orchiectomy or vasectomized with appropriate post-vasectomy documentation of 
absence of sperm in ejaculate. 


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Female patients or partners of male patients are considered to be of childbearing potential 
unless 1 of the following applies: 
• Considered to be permanently sterile. Permanent sterilization includes hysterectomy, 
bilateral salpingectomy, and/or bilateral oophorectomy; or 
• Is postmenopausal, defined as no menses for at least 12 months without an alternative 
medical cause. A high follicle-stimulating hormone (FSH) level consistently in the 
postmenopausal range (30 mIU/mL or higher) may be used to confirm a postmenopausal 
state in women not using hormonal contraception or hormonal replacement therapy; 
however, in the absence of 12 months of amenorrhea, a single FSH measurement is 
insufficient to confirm a postmenopausal state. 
 
Female and male patients of reproductive potential must practice highly effective methods 
(failure rate < 1% per year) of contraception with their partners, if of reproductive potential, 
during treatment and for 6 months following the last dose of rucaparib or longer if required 
for the second study drug, or longer if requested by local authorities. Highly effective 
contraception includes the following: 
• Ongoing use of progesterone only injectable or implantable contraceptives; 
• Placement of an intrauterine device (IUD) or intrauterine system (IUS); 
• Bilateral tubal occlusion;  
• Sexual abstinence as defined as complete or true abstinence, acceptable only when it is 
the usual and preferred lifestyle of the patient; periodic abstinence (eg, calendar, 
symptothermal, post-ovulation methods) is not acceptable; or 
• Male sterilization, with appropriate post vasectomy documentation of absence of sperm 
in ejaculate. 
 
Patients will be instructed to notify the investigator if pregnancy in either the patient or 
partner is discovered either during or within 6 months of completing treatment with study 
drug or longer if required for the second study drug. 
4.2 
Waivers of Inclusion/Exclusion Criteria 
No waivers of these inclusion or exclusion criteria will be granted by the investigator and the 
sponsor or its designee for any patient enrolling into the study. 
 
 


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5 
RUCAPARIB TREATMENT 
This section describes the treatment of rucaparib across all treatment arms. The treatment 
descriptions of the second study drug administered in combination with rucaparib are 
provided in Section 8.X.6 of the respective treatment arm. 
5.1 
Rucaparib Description of Treatment and Storage 
Rucaparib camsylate (also known as CO-338; formerly known as PF-01367338 and 
AG-014447) is an oral formulation. Rucaparib tablets for oral administration will be supplied 
to the study sites by the sponsor. A brief description of rucaparib is provided below with 
details in the Pharmacy Manual. 
Table 5-1. 
Description of Rucaparib Tablets 
Drug Name 
Rucaparib 
INN 
Rucaparib 
Formulation  
(strengths expressed as 
free base) 
Tablet; film coated; 200 mg (blue, round, debossed with C2), 250 mg 
(white, diamond shape, debossed with C25), 300 mg (yellow, oval, 
debossed with C3).  
How Supplied 
200 mg, 250 mg, and 300 mg (as free base) strength tablets in 60 count 
bottles. Patients may receive one or more strengths.  
Storage Conditions 
15–30°C (59–86°F). 
 
5.2 
Rucaparib Packaging and Labeling 
Rucaparib tablets are provided in 60-count high-density polyethylene (HDPE) bottles with 
child resistant caps and should be stored in the provided containers between 15° and 30°C 
(59 and 86°F). Patients will be dispensed one or more strengths depending on their current 
dose of rucaparib. The number of bottles of each strength dispensed will be sufficient to 
supply 28 days treatment per cycle, including a small overage. 
Details with respect to packaging and labeling of rucaparib tablets are described in the 
Pharmacy Manual. 
5.3 
Blinding/Masking of Treatments 
This is an open-label study; the investigational products will not be blinded or masked. All 
patients enrolled will receive rucaparib in combination with the second study drug in the 
specified treatment arm. 
5.4 
Method of Assigning Patients to Treatment Arms 
Refer to Section 3.1.2 for a description of the enrollment process. 
After confirming that patients fulfill eligibility criteria, the investigator or his/her delegate 
will enroll patients into the available combination cohorts.  


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5.5 
Preparation and Administration of Rucaparib 
For Phase 1b of each treatment arm, rucaparib will be administered orally at the dose and 
frequency specified by the dose cohort to which the patient is enrolled (see Section 8.X.4.2.1 
of the respective treatment arm). 
For Phase 2 of each treatment arm, rucaparib will be administered orally at the RP2D for that 
combination. As rucaparib is dosed BID, the dose should be administered as close to 
12 hours apart as possible, preferably at the same times every day with at least 8 ounces 
(240 mL) of water starting on Cycle 1 Day 1. Study drug (tablets) may be taken with or 
without food. Tablets should be swallowed whole without crushing or chewing.  
Rucaparib will be provided as 200, 250, and 300 mg [as free base] dose strength tablets. If a 
patient vomits after dosing, the dose will not be made up; the patient will take their next dose 
at the regularly scheduled interval. 
Treatment will begin on Day 1 of Cycle 1. Patients will be provided a sufficient quantity of 
rucaparib to last until Day 1 of the next treatment cycle. Patients will be instructed to bring 
their study drug tablets and all containers (empty, partially used, and/or unopened) to the next 
scheduled visit for reconciliation by site personnel. 
5.6 
Dose Modification Criteria for Rucaparib Combinations 
Study drug dose modification criteria are described within each specific treatment arm 
(Section 8.X.6.4). 
5.7 
Treatment Compliance 
Documentation of dosing will be recorded in a study-specific dosing diary provided by the 
sponsor (or designee). Dosing noncompliance is defined as a patient missing > 14 days of 
study drug within a cycle for 2 consecutive cycles for reasons other than toxicity. The 
sponsor may require patients meeting noncompliance criteria to discontinue study treatment. 
Study site personnel will review dosing information with the patient (or legally authorized 
representative) on scheduled clinic visit days, providing instructions regarding dose, dose 
frequency and the number of tablets to be taken for each dose. Patients (or legally authorized 
representative) will be instructed to keep all unused tablets and containers (empty, partially 
used, and/or unopened) for accountability at the next scheduled clinic visits. A compliance 
check and tablet count will be performed by study personnel during clinic visits. Additional 
descriptions of compliance for the second study drug are in Section 8.X.6, where applicable. 
Details regarding study drug dispensation and return can be found in the study-specific 
Pharmacy Manual. 
Every effort should be made to ensure patients return to the clinic with their study drug 
containers/ unused study drug at the end of each cycle of treatment. Study site personnel 
should conduct a verbal review of dosing with the patient and document the discussion in the 
patient’s medical record. This may serve as source documentation for the purpose of entering 
dosing data on the appropriate eCRF. 


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5.8 
Accountability of Protocol-specified Treatment 
Study personnel will maintain accurate records of study drug receipt, dispensation, use, 
return, destruction, and reconciliation of study drugs provided by the sponsor. The interactive 
response technology (IRT) system will be used to manage study drug inventory at all sites. In 
order to function properly, the system will require real time entry of study drug receipt, 
dispensation, destruction, etc. by study personnel at the study site. 
The site is responsible for the return or destruction of study drug supplied by the sponsor. 
Authorization to destroy study drug at the site that has not been dispensed to a patient (eg, 
expired study drug), must be requested from the sponsor prior to destruction. All study drug 
containers must be accounted for prior to their destruction at the study center, according to 
institutional procedures for disposal of hazardous materials. Unused and returned study drug 
product and containers should be destroyed on-site if possible. If destruction on site is not 
possible, supply should be returned to the drug depot, following the sponsor’s instructions. 
During the course of the study and at completion of the study, the number of study drug units 
(ie, bottles, vials) and containers received, dispensed, returned, and destroyed must be 
recorded and reconciled. Additional details regarding study drug accountability can be found 
in the Pharmacy Manual. 
5.9 
Investigational Treatment beyond Disease Progression 
Patients will receive study drug(s) until confirmed radiologic disease progression as assessed 
by investigator using RECIST v1.1 criteria, unacceptable toxicity, patient or physician 
request to discontinue, death, initiation of any other anticancer therapy, positive pregnancy 
test, or termination of the study (refer to Section 3.2). 
If a patient receiving study drug(s) has met criteria for confirmed radiologic disease 
progression by RECIST v1.1, but the patient continues to derive clinical benefit per the 
investigator, then continuation of study drug(s) may be permitted upon discussion with the 
medical monitor. In such cases, the documented decision to continue will be made jointly 
between the investigator and the sponsor (or designee), it must be documented in the 
patient’s chart, and the patient must provide consent within a reasonable timeframe of the 
documented decision to continue study treatment. Clinical scenarios where continuation of 
study drug(s) after radiographic progression may be considered include, but are not limited to 
1) a patient for whom radiographic progression develops slowly while disease-related 
symptoms remain well controlled; 2) a patient who experiences progression in a site of 
disease that is unlikely to adversely affect prognosis (eg, enlargement of a solitary lymph 
node); or 3) a patient with general disease control, but limited progression in sites of disease 
that can be managed with local therapies such as surgery or radiation. Patients continuing to 
receive study drug(s) will continue to have all protocol-required assessments as described in 
Section 7 and Section 8 of the respective treatment arm. 
 
 


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6 
PRIOR AND CONCOMITANT THERAPY 
The protocol specification for prior and/or concomitant therapy that are general to all 
treatment arms are provided below. Additional information or specifications unique to a 
treatment arm are provided in Section 8.X.7 of the respective treatment arm. 
6.1 
Supportive Care 
During the study, supportive care (eg, antiemetics, analgesics for pain control, antidiarrheals, 
thyroid replacement hormone, hematopoietic growth factors, blood products) may be used at 
the investigator’s discretion and in accordance with institutional procedures. Drugs with a 
known risk for prolonged QT interval and Torsades de Pointes should be avoided. Supportive 
care must be recorded for each patient in the appropriate section of the eCRF.  
Erythropoietin, darbepoetin alfa, and/or hematopoietic colony-stimulating factors for 
treatment of cytopenias should be administered per standard of care and according to 
institutional guidelines. Transfusion thresholds for blood product support will be in 
accordance with institutional guidelines. 
All procedures performed (eg, thoracentesis, etc.) during the study must be documented on 
the eCRF. 
6.2 
Radiotherapy 
Palliative radiotherapy on lesions not considered target lesions for tumor evaluation is 
permitted during the study. Treatment with study drug should be held prior to initiation of 
radiation therapy and until the patient has recovered from any radiation related toxicity. 
6.3 
Anticancer or Experimental Therapy 
No other anticancer therapies (including chemotherapy, radiation, antibody or other 
immunotherapy, gene therapy, vaccine therapy, angiogenesis inhibitors, or other 
experimental drugs) of any kind will be permitted while the patient is participating in the 
study, with the exception of palliative radiotherapy and hormonal treatment. Prior treatment 
with such excluded anticancer therapies must have been completed > 14 days prior to the 
first dose of study drug or as specified in the treatment arm-specific inclusion/exclusion 
criteria (Section 8.X.5). 
Any botanical preparations (eg, herbal supplements or traditional Chinese medicines) 
intended to treat the disease under study or provide supportive care are prohibited (except 
those prescribed as supportive care by a health care professional as per Section 6.1). 
6.4 
CYP450 Isoenzyme Inhibitors, Inducers, and Substrates 
Based on the results from the in vivo CYP interaction study (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 medications that 
are sensitive clinical substrates of CYP1A2, CYP2C9, CYP2C19, and/or CYP3A (refer to 


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the rucaparib IB, Section 6.4). Selection of an alternative concomitant medication is 
recommended. 
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 (refer to rucaparib IB, Section 6.4). 
6.5 
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 international normalized ratio (INR) monitored regularly per standard clinical practice. 
6.6 
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 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 MATE-1 and MATE-2-K, a moderate inhibitor of 
OCT1, and a weak inhibitor of OCT2. As inhibition of these transporters could increase 
metformin renal elimination and decrease liver uptake of metformin, caution is advised when 
metformin is co-administered with rucaparib. In addition, rucaparib is an inhibitor of the 
BCRP with concentration of inhibitor required for 50% inhibition (IC50) value suggesting 
potential BCRP inhibition and increased exposures of medicinal products that are BCRP 
substrate (eg, rosuvastatin). 
6.7 
Imaging Restrictions and Precautions 
It is the local imaging facility’s responsibility to determine, based on patient attributes (eg, 
allergy history, diabetic history, and renal status), the appropriate imaging modality and 
contrast regimen for each patient. Oral and/or intravenous (IV) contrast should be used 
whenever possible and appropriate, and rectal contrast should only be considered in patients 
with peritoneal disease. Imaging contraindications and contrast risks should be considered in 
this assessment. Patients with renal insufficiency should be assessed as to whether or not they 
should receive contrast and if so, what type and dose of contrast is appropriate.  


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The ultimate decision to perform MRI in an individual patient in this study rests with the site 
radiologist, the investigator and the standard set by the local Independent Ethics Committee 
(IEC). 
6.8 
General Restrictions 
Photosensitivity has been observed in patients treated with rucaparib. Patients should avoid 
spending time in direct sunlight because they burn more easily during treatment with 
rucaparib. When outdoors, patients should use typical precautions such as applying sunscreen 
(sun protection factor 50 or greater) and/or covering exposed skin with clothing and wearing 
a hat and sunglasses. 
7 
METHODS OF DATA COLLECTION 
7.1 
Medical History and Demographic/ Baseline Characteristics 
Basic demographic and baseline characteristics will be collected during screening. In 
addition to the evaluation of a patient’s medical history in terms of study eligibility, all 
relevant medical conditions will be documented on the appropriate eCRF. Events that occur 
after signing of informed consent but prior to initiation of study drug(s), unless due to a 
protocol-mandated procedure, should be recorded on the Medical History eCRF.  
The patient’s entire oncology history will be collected on the appropriate eCRF including 
cancer histology, stage, and date of diagnosis, prior surgeries/ treatments received for cancer, 
dates of treatment administration, best response achieved, date of progression and how 
assessed, radiology reports, and HRD status. 
7.2 
Prior and Concomitant Medication Assessments 
Medications being used by the patient will be recorded as prior medications during screening 
and as concomitant medications following receipt of the first dose of study drug through the 
completion of the last Safety Follow-up Visit after treatment discontinuation. Medication 
information will be entered in the appropriate eCRF after it is obtained at each study visit. 
7.3 
Efficacy Evaluations 
7.3.1 
Disease/ Tumor Assessments 
Tumor assessment measurements will be performed at screening and at the end of the 
treatment arm-specified interval starting with Cycle 1 Day 1 until objective radiological 
disease progression (refer to Section 8.X.4.2 for assessment intervals). Tumor assessments 
should be performed at the time of treatment discontinuation if the reason for discontinuation 
was other than radiologically-confirmed disease progression and the time elapsed since the 
last assessment is greater than the tumor-assessment interval. In addition, tumor assessments 
should be made as clinically indicated. All responses (CR or PR) must be confirmed with a 
scan no less than 4 weeks after the initial response. 


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Disease assessment will comprise clinical examination and appropriate imaging techniques 
per RECIST v1.1 (CT and/or MRI scans of the chest, abdomen, and pelvis with appropriate 
slice thickness per RECIST). Other complementary assessments (X-ray, positron emission 
tomography [PET], and ultrasound) may be performed if required. If a 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. The same methods used to detect lesions at baseline are to be used to follow 
the same lesions throughout the clinical study. CT/MRI scans of the chest, abdomen, and 
pelvis performed to determine the extent of disease at baseline should also be performed at 
each time of disease assessment, even if the scans were negative at baseline. Investigators 
should perform scans of other anatomical sites that, in their judgment, are appropriate to 
assess based on each patient’s tumor status. If a patient has known brain metastases, this 
disease should be evaluated at each required assessment time. Tumor markers should be 
collected as clinically indicated for the response assessment by RECIST v1.1. For example, a 
complete response (CR) in an ovarian cancer patient would require normalization of cancer 
antigen-125 (CA-125). 
Tumor response will be interpreted using RECIST v1.1. Disease progression will be 
determined by RECIST v1.1. If the radiologic assessment does not confirm disease 
progression, patients should continue on treatment and continue to be assessed by RECIST 
v1.1 per the protocol schedule of assessments. 
Patients who discontinue treatment for a reason other than disease progression or death 
should continue to have tumor scans performed at the interval specified for that treatment 
arm until radiological disease progression as assessed by the investigator, death, loss to 
follow-up, withdrawal from study, study termination, or initiation of subsequent anticancer 
treatments. 
7.4 
Safety Evaluations 
7.4.1 
Adverse Event Assessment 
The investigator has the responsibility for assessing the safety of the patients and for 
compliance with the protocol to ensure study integrity. During the screening period, unless 
otherwise required by local regulations, serious adverse events (SAEs) which are related to 
protocol-mandated assessments will be reported. Once enrolled and study drug is 
administered, patients will be monitored for all AEs, SAEs, and AESIs (as defined in the 
respective IBs) during study participation and until last Safety Follow-up Visit(s).  
After the last Safety Follow-up Visit(s), only treatment-related SAEs (including serious 
reports of pneumonitis or similar events, ie, interstitial lung disease, pulmonary fibrosis, 
acute interstitial pneumonitis, alveolitis necrotizing, alveolitis, hypersensitivity pneumonitis, 
and organizing pneumonia, if considered to be related to study drug), and AESIs of MDS and 
AML, irrespective of causality, need to be reported. Any ongoing SAEs, AESIs, or 
treatment-related Grade 3/4 AEs will be followed until resolution or stabilization, death, or 
until loss to follow up. AEs and laboratory abnormalities will be graded according to the NCI 
CTCAE grading system (v5.0) and recorded on the eCRF. 


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Complete details for monitoring AEs, including the definition of drug-related AEs, are 
provided in Section 10. 
7.4.2 
Clinical Laboratory Investigations 
The clinical laboratory assessments will be general across the combination treatment arms. 
Any additional laboratory assessment(s) specific to a treatment arm will be described in 
Section 8.X.8.2 of the respective arm. 
All clinical laboratory samples for safety will be collected and analyzed by the site’s local 
laboratory. The panels of laboratory tests to be performed are presented in Table 7-1. 
Laboratory tests will be assessed for all patients at screening, during treatment per the 
Schedule of Assessments described for the respective treatment arms, and at the End of 
Treatment Visit, and Safety Follow-up Visit(s), and if toxicities are present.  
Laboratory tests performed within the protocol-defined assessment windows (-3 days for 
each timepoint) do not need to be repeated on the day of the visit. Further, screening 
laboratory tests performed within 3 days of C1D1 do not have to be repeated at C1D1.   
Hematology and chemistry results must be reviewed by the investigator before the start of 
study drug(s) and throughout the study. Fasting is not required before blood sampling for 
chemistry tests. Additional and more frequent tests may be performed at the investigator’s 
discretion. 
Table 7-1. 
Laboratory Tests - All Treatment Arms 
Hematology 
Clinical Chemistry 
Red blood cell (RBC) count 
Total protein 
Glucose 
Hemoglobin 
Albumin 
Sodium 
Hematocrit 
Creatinine (eGFR)a 
Potassium 
MCV 
Blood urea nitrogen (BUN) or urea 
Magnesium 
MCH 
Bilirubin (total, direct, indirect) 
 
Chloride 
MCHC 
Alkaline phosphatase (ALP) 
Bicarbonate (CO2/HCO3-) 
Reticulocyte count 
Alanine aminotransferase (ALT) 
Calcium 
White blood cell (WBC) count 
Aspartate aminotransferase (AST) 
Phosphorus 
Differential with absolute 
neutrophil count (ANC) 
Lactate dehydrogenase (LDH) 
Total cholesterol 
Platelet count 
Treatment Arm A only: Thyroid stimulating hormone (TSH) and 
free triiodothyronine (T3)/free thyroxine (T4) 
Abbreviations:  eGFR = estimated glomerular filtration rate; MCH = mean corpuscular hemoglobin; 
MCHC = mean corpuscular hemoglobin concentration; MCV = mean corpuscular volume. 
a 
Estimated GFR using the Cockcroft Gault formula (Appendix 1) or institutional standard formula may 
also be collected, as clinically applicable. 


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Urinalysis: performed locally on a freshly voided clean sample by dipstick for protein, 
glucose, blood, pH, and ketones. If dipstick findings are abnormal based on the investigator’s 
judgment, then a microscopic evaluation or 24-hour urine collection will be performed to 
assess the abnormal findings. Urinalysis will be performed at screening for all treatment 
arms, and for Treatment Arm A, at Day 1 and Day 15 for Cycles 1 and 2, Day 1 at cycles 
thereafter, and at the End of Treatment Visit. Urinalysis may be conducted at other times as 
clinically indicated.  
Pregnancy Testing: Female patients of childbearing potential must have a negative serum or 
plasma pregnancy test result ≤ 3 days prior to administration of the first dose of study drug. 
In addition, a blood-based pregnancy test must be performed ≤ 3 days prior to Day 1 of every 
cycle during the Phase 1b or Phase 2 Treatment Phases and at the time of treatment 
discontinuation.  
Local laboratory reports will be reviewed by the investigator or delegated physician who will 
then comment on out of range parameters and assess clinical significance. Clinically 
significant abnormalities and associated panel results, as well as results of any additional 
tests performed as follow up to the abnormalities, will be documented on the eCRF as an AE. 
Refer to Section 10.5 for guidelines on reporting of abnormal laboratory values as AEs. 
7.4.3 
Vital Signs 
Vital signs will include blood pressure, pulse, and body temperature and will be taken after 
the patient has been resting for at least 5 minutes during screening, at study visits during the 
Treatment Phase, and at the End of Treatment Visit, and more often if required in 
Section 8.X.8.1 of the respective treatment arm. Oxygen saturation will be measured if 
clinically indicated. 
7.4.4 
12-Lead Electrocardiogram 
For all patients, local 12-lead ECGs will be taken at screening, Day 1 of each cycle, and at 
the End of Treatment Visit. ECGs are to be performed at rest in the supine position. 
The following will be measured or calculated: heart rate, PR, QRS, QT, QT interval 
corrected using Fridericia's method (QTcF), and rhythm. The investigator or qualified 
designee will review the ECGs locally and assess the results as normal or abnormal 
(clinically significant or not clinically significant). 
If it is clinically indicated, ECGs can be performed at other times during the study. 
7.4.5 
Physical Examinations, Body Weight, and Height 
Physical examinations will include an assessment of all the major body systems. Complete 
physical examinations will be performed during screening and at the End of Treatment Visit. 
Physical examinations at study visits during the Treatment Phase will be limited as clinically 
indicated. 


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Height will be measured during the Screening Visit only. Weight will be measured per 
institutional guidelines during screening, on Day 1 of each cycle, and at the End of Treatment 
and Follow-up Visits. 
7.4.6 
ECOG Performance Status 
ECOG performance status will be assessed during screening, at study visits during the 
Treatment Phase, End of Treatment, and Follow-up Visits. The ECOG performance status 
should be assessed by the same study personnel at each visit, if possible. For eligibility 
purposes, patients with borderline ECOG performance status should be considered carefully 
to avoid enrolling patients who may have significant impairment. 
7.5 
Biomarker Evaluations 
7.5.1 
Mandatory Tumor Tissue Analysis 
Patients must have sufficient archival or more recently obtained formalin-fixed, paraffin-
embedded (FFPE) tumor tissue (obtained prior to administration of any study drug) available 
for molecular analyses. Tumor tissue must be submitted to the sponsor’s central laboratory 
by Cycle 2 Day 1, but the results are not required from the central laboratory prior to 
enrollment.  
Submission of approximately 10 to 15 × 5 µm unstained sections (or equivalent) for 
biomarker analyses is preferred. FFPE blocks that contain a similar tumor volume are 
acceptable if sections cannot be prepared locally. Be advised that it may take up to 3 months 
for block returns to allow the sponsor to have sections made. The tumor tissue sample must 
be of adequate quality (at least 20% tumor content [≥ 30% is strongly preferred] with a 
minimum of 80% nucleated cellular content), or a new sample must be obtained. Please 
check with the sponsor if the sample does not meet all of these requirements. Refer to the 
Laboratory Manual for details on tissue adequacy, sample collection and handling 
instructions.  
Collection of a tumor tissue sample at or following disease progression until the start of the 
next treatment is optional; patients must provide additional consent for this optional tumor 
tissue biopsy sample. If disease progression is caused by appearance of a new lesion(s), the 
lesion(s) should be prioritized for the optional biopsy. Refer to the Laboratory Manual for 
details. 
The tumor specimens may be sent to 1 or more laboratories and evaluated for alterations in 
cancer-related genes or other genomic signatures (eg, percentage of genomic LOH) by 
targeted next-generation sequencing (NGS) or whole genome sequencing. Additional 
genomic, transcriptional, and/or proteomic profiling may also be performed. The goal of 
these biomarker analyses is to identify molecular markers associated with response or 
resistance to the combination of rucaparib and the second study drug.  


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7.5.2 
Plasma ctDNA Analysis 
Blood samples will be collected during screening, before dosing on Day 1 of Cycles 1 
through 6; subsequent sampling will occur at approximately the same time as radiological 
imaging and CA-125 sampling, where applicable (± 3-day window), the End of Treatment 
Visit, and 28-day Follow-up Visit. Sample collection details will be provided in the 
Laboratory Manual. These samples will be used for ctDNA profiling to assess alterations in 
genes that may be associated with response and resistance to the combination of rucaparib 
and the second study drug. 
7.5.3 
Pharmacogenomics 
A blood sample for pharmacogenomics analyses will be collected at Cycle 1 Day 1 (or next 
visit if not collected at Cycle 1 Day 1) from all patients. Sample collection details will be 
provided in the Laboratory Manual. Results of actionable alterations may be made available 
to the investigator, subject to patient’s consent. 
These samples, if needed, will be used for the evaluation of genes or biomarkers that may 
affect the PK of rucaparib, the second study drug, or metabolites. Pharmacogenomic samples 
may also be tested to determine whether any mutations identified from genomic testing are of 
germline origin. Because the germline analysis will be done near the end of the study, there 
are no plans to share these results with the investigator and the patient. However, if an 
actionable mutation, as defined by the American College of Medical Genetics and Genomics 
(https://www.ncbi.nlm.nih.gov/clinvar/docs/acmg/), is detected, the incidental finding will be 
made available to the investigator provided the results are generated from a Clinical 
Laboratory Improvement Amendments (CLIA)-certified laboratory and the patient has 
consented to receive the results. 
7.5.4 
Additional Research 
The patient will have the option to provide additional consent to allow the sponsor to retain 
residual samples for future unspecified research. 
7.6 
Other Study Evaluations 
Pharmacokinetic assessments, biomarker evaluations, and other treatment arm-specific data 
collection are described in Section 8.X.8 of the respective treatment arm. 
 
 


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8.A TREATMENT ARM A: RUCAPARIB AND LUCITANIB 
 Angiogenesis Inhibition 
Tumor angiogenesis is a complex process through which new blood vessels are formed from 
the pre-existing vasculature of the tumor and necessary for metastatic dissemination.26,27 The 
process of angiogenesis is critically important for maintaining tumor oxygenation, delivery of 
nutrients, including growth factors and hormones, and tumor metabolic waste removal.28 
Several growth factors are key players in promoting tumor angiogenesis. These growth 
factors, secreted by tumor cells and/or the tumor microenvironment, stimulate endothelial 
cells to proliferate and form new blood vessels. They include vascular endothelial growth 
factor (VEGF), fibroblast growth factor (FGF), and platelet derived growth factor (PDGF), 
among others. They regulate fundamental developmental pathways, which make them and 
their cognate receptors important cancer therapeutic targets.  
VEGF, a cytokine that is present in various human tumors and a potent inducer of vascular 
permeability, plays an important role in tumor angiogenesis.29,30 Activation of the 
VEGF/VEGFR pathway promotes endothelial cell growth, migration, and survival; as well, it 
mediates vessel permeability and mobilizes endothelial progenitor cells. VEGF acts by 
binding to several high-affinity transmembrane endothelial cell receptors, most notably 
VEGFR 1 (Flt 1) and VEGFR 2 (KDR). In addition, VEGF binding to VEGFR 3 (Flt 4) 
expressed on the lymphatic endothelium, initiates lymphangiogenesis, which contributes to 
tumor growth, invasion, and metastasis.31 The expression of angiogenic growth factor 
inhibitors, like VEGF, are upregulated in many tumors, and the activation of the associated 
growth factor receptors have been shown to correlate with the degree of tumor 
vascularization; as such VEGF expression has been proposed as a prognostic factor in patient 
survival.32 VEGF is therefore considered to be an important therapeutic target in 
anti-angiogenic cancer therapy strategy, and drugs affecting the function of VEGFRs (eg, 
ligand interaction or kinase activity) have been developed and approved, with multiple agents 
and indications.33-37 
Therapies directed against VEGF and its receptors exert their effects through a number of 
potential mechanisms, including (1) inhibition of new vessel growth; (2) regression of newly 
formed tumor vasculature; (3) alteration of vascular function and tumor blood flow; and (4) 
direct effects on tumor cells.38,39 The VEGF inhibitor, bevacizumab (AVASTIN®), is 
approved in combination with platinum-based chemotherapy, followed by single-agent use, 
for first-line treatment of ovarian cancer and for platinum-sensitive recurrent disease. It has 
also been shown to benefit patients with recurrent platinum-resistant disease in combination 
with chemotherapy.40,41 
Angiogenesis inhibitors, such as VEGFR inhibitors, combined with PARP inhibitors have 
suggested synergistic effects in nonclinical studies conducted by the sponsor (Clovis, data on 
file), as well as by other researchers.42-44 VEGF overexpression has a role in the development 
of ovarian cancers.45 It has been hypothesized that combination therapies including 
angiogenesis inhibitors and PARP inhibitors can induce a higher incidence of hypoxia, a 
reduction in homologous recombination, and subsequently a higher sensitivity to PARP 
inhibition.42 Inhibition of VEGFR3 can also result in down-regulation of BRCA1 and 


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BRCA2 expression.46 PARP inhibitors in combination with targeted anti-angiogenic agents 
have been well-studied in patients with breast and ovarian cancer.9,47,48 
 Lucitanib Background 
Overviews of data from nonclinical and clinical studies are provided below and described in 
detail in the lucitanib IB. 
8.A.2.1 
Mechanism of Action of Lucitanib 
Lucitanib is a potent, selective inhibitor of the tyrosine kinase activity of vascular endothelial 
growth factor receptors, types 1, 2, and 3 (VEGFR1–3); platelet-derived growth factor 
receptors (PDGFR), types alpha and beta (PDGFRα/β); and fibroblast growth factor 
receptors (FGFR), types 1, 2, and 3 (FGFR1–3).  
8.A.2.2 
Nonclinical Experience 
In vivo, the oral administration of lucitanib over a range of well-tolerated doses significantly 
inhibited tumor growth in subcutaneous xenograft rodent models using a panel of human 
tumor cell lines or primary patient-derived tumors. In addition, the combination of lucitanib 
with a PARP inhibitor demonstrated enhanced anti-tumor responses in murine models. 
Lucitanib demonstrated anti-angiogenic activity with regard to modification of tumor 
perfusion, expression changes in tumor vasculature markers in subcutaneous xenograft 
models, and inhibition of FGF-induced angiogenesis in Matrigel™ implanted mice. 
Lucitanib showed no significant inhibition when evaluated in vitro in a broad screen against 
receptors, ion channels, enzymes, and transporters suggesting that unexpected 
pharmacological activity is unlikely based on the IC50 obtained and on available tissue 
distribution data. 
Lucitanib is metabolized by both oxidative and conjugation routes. The in vitro metabolism 
of lucitanib was mainly CYP dependent with equal contribution of CYP2C8 and CYP3A4. 
Based on clinical DDI knowledge and in vitro-in vivo scaling, an increase in lucitanib 
exposure is expected in case of co-administration of lucitanib with strong inhibitors of 
CYP3A4 or CYP2C8 and strong dual inhibitors of CYP3A4/CYP2C8. Therefore, 
concomitant use of lucitanib with these medications is contraindicated. Additionally, the 
concomitant use of lucitanib with moderate inhibitors of CYP3A4 or CYP2C8 and dual 
inhibitors of CYP3A4/CYP2C8 is not recommended, and if clinically necessary, should be 
used with caution. Strong inducers of CYP3A4 may reduce the plasma concentrations of 
lucitanib and are contraindicated. 
At the observed plasma concentrations of lucitanib at 10 mg QD, the risk of clinical DDI 
with lucitanib as a CYP inhibitor is low. No CYP induction by lucitanib was observed in 
vitro at clinically relevant lucitanib concentrations. 
Lucitanib was shown to be a substrate of P-gp. However, due to its high permeability across 
Caco-2 cell monolayers, no DDI is expected with drugs that are P-gp inhibitors. Lucitanib 


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was not a substrate of sodium/taurocholate cotransporting polypeptide (NTCP), organic 
anion transporting polypeptide (OATP), organic anion transporter (OAT)2, organic cation 
transporter (OCT)1, or breast cancer resistance protein (BCRP). The potential for lucitanib to 
cause DDIs with inhibitors of the transporters tested is low. Further, in vitro 
transporter-inhibition data suggested that lucitanib has a low risk of clinically relevant 
inhibition of uptake and efflux transporters. 
Lucitanib was found to be genotoxic in Ames tests and demonstrated clastogenicity in human 
lymphocytes in vitro. Although no embryofetal toxicology assessment has been conducted 
with lucitanib, it is considered a reprotoxicant.  
8.A.2.3
Clinical Experience 
The initial focus of the lucitanib clinical development program (CDP) was the treatment of 
patients with advanced/metastatic breast cancer that harbored an FGFR gene alteration. Five 
Phase 1 and 2 studies have been conducted to evaluate oral lucitanib as monotherapy in the 
treatment of cancer in patients with predominately FGF alterations. These studies have 
evaluated the safety, efficacy, pharmacodynamics, and PK of lucitanib at continuous doses 
ranging from 5 mg QD to 30 mg QD and in intermitted dosing schedules of 21 days on and 
7 days off (21/7).  
Results from the first study, a Phase 1 dose escalation (Study CL1 80881-007), identified 
30 mg QD as the MTD and a RP2D of 20 mg QD; however, due to the incidence of 
hypertension and proteinuria at the higher dose levels, the recommended dose was reduced to 
15 mg QD and later to 10 mg QD for all ongoing lucitanib studies. 
Three of the 5 studies (CL2-80881-001 [BIG 2-13/FINESSE], CL2-80881-002 [INES], and 
CO-3810-025) evaluated lucitanib administration to patients with metastatic breast cancer. 
The fifth study (Study E-3810-II-02) was a Phase 2, open-label study of oral lucitanib in 
patients with advanced/metastatic small cell lung cancer (SCLC) and non-small cell lung 
cancer (NSCLC) and FGF, VEGF, or PDGF genetic alterations.  
A total of 424 patients received at least 1 dose of lucitanib with 421 patients exposed at or 
above the recommended monotherapy dose of 10 mg QD. 
8.A.2.3.1
Clinical Pharmacology 
The clinical PK properties of lucitanib were evaluated following single and multiple daily 
oral administrations. Lucitanib was rapidly absorbed with a Cmax reached within 1 to 3 hrs. 
Following oral administration of lucitanib, Cmax and AUC0-24 increased approximately dose 
proportionally with relatively high inter-patient variability. 
Lucitanib showed a long terminal half-life (t1/2) of 31 to 40 hrs, low apparent clearance 
(CL/F), and moderate apparent volume of distribution (V/F) in patients. At steady state 
following daily dosing, lucitanib showed approximately 2-fold accumulation.   


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Lucitanib has high plasma protein binding (99.3%). No major metabolite of lucitanib was 
observed. The observed transformations of the lucitanib were demethylation, 
glucuronidation, glucosidation, and hydroxylation. 
Based on clinical concentration-QT analysis, no significant drug-related increase in 
Fridericia-corrected QT interval from baseline (ΔQTcF) was observed following oral 
administration of 10 mg lucitanib QD.  
8.A.2.3.2 
Efficacy 
Activity was observed across a wide range of tumor types in the lucitanib Phase 1, 
first-in-human study.49 In the subsequent Phase 2 studies evaluating lucitanib monotherapy, 
only modest clinical efficacy was observed in lung and breast cancer patients across all 
lucitanib clinical studies and at all doses. 
The combined efficacy analysis demonstrates an ORR of 9.3% and median PFS of 
15.9 weeks (95% CI, 13.4-19.1). The median time to response was 8 weeks (range, 4-
96 weeks) and median duration of response of 37.7 weeks (95% CI, 18.4-101.0). Efficacy 
was not significantly different for the subset of breast cancer patients only (N = 257), with an 
ORR of 8.9%, clinical benefit rate (CBR) of 18.3%, and median PFS of 14.1 weeks (95% CI, 
12.0-16.4). 
8.A.2.3.3 
Safety 
A total of 424 patients received at least 1 dose of lucitanib and were included in a pooled 
safety analysis.  
The most frequently reported (≥ 30%) TEAEs were hypertension, nausea, hypothyroidism, 
proteinuria, diarrhea, decreased appetite, headache, asthenia/fatigue, and vomiting. Most of 
these events were assessed as Grade 1 or 2, except for hypertension, where the majority of 
patients with a hypertension event had a Grade 3 event. The AEs most frequently reported as 
related to study drug were similar to the most frequently reported AEs (≥ 30%), regardless of 
severity. 
Twenty-six patients (6.1%) had at least one AE with a fatal outcome with none assessed as 
related to lucitanib treatment. Of the 424 patients in the safety population, 44.3% had at least 
1 SAE, with the most frequent SAEs being dyspnea, thrombotic microangiopathy, and 
hypertension. All-grade hypertension was reported in over 80% of all patients and in over 
50% with ≥ Grade 3 severity. Approximately 20% of patients had an TEAE that lead to study 
drug discontinuation, with hypertension the most common at an incidence of 3.5%. 
Overall, the observed clinical risk profile for lucitanib is consistent with its mechanism of 
action and AE reported for other anti-angiogenic drugs, as well as observations from the 
nonclinical studies, with AEs mainly targeting the kidney, cardiovascular system, 
gastrointestinal tract, and thyroid gland.  
Adverse drug reactions (ADRs) for lucitanib are presented in the lucitanib IB (Section 6).  


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8.A.2.3.3.1 
Hypertension 
Hypertension is a known toxicity associated with VEGF inhibitor treatment, including 
lucitanib.50,51 
Hypertension is the most frequently reported treatment-related AE reported for lucitanib 
monotherapy in Phase 1-2 clinical studies. Rapid increases in blood pressure (BP) from 
baseline were observed as early as the first few days following initiation of lucitanib. 
Hypertension is generally manageable through judicious use anti-hypertensive treatment and 
rarely results in permanent treatment discontinuation. Abnormal BP measurements in the 
clinic should be repeated within an hour to confirm findings. Additionally, patients should be 
instructed to self-measure and record their BP at home in a diary log at least 2 times per week 
while receiving lucitanib treatment. Patient-monitored BP should be followed by the 
Investigator at all clinic visits to evaluate the effectiveness of any concomitant anti-
hypertensive treatment. Guidelines for management of lucitanib-related hypertension are 
provided in Section 8.A.6.5.1. 
8.A.2.3.3.2 
Thrombotic Microangiopathy 
Thrombotic microangiopathy (TMA) has been observed with other anti-angiogenic 
compounds. If TMA is suspected, lucitanib dosing should be interrupted and a kidney biopsy 
should be performed, as needed, to confirm the diagnosis; a nephrologist should be 
consulted, as appropriate. If TMA is confirmed, lucitanib should be permanently 
discontinued. 
8.A.2.3.3.3 
Proteinuria 
Proteinuria is an identified risk for lucitanib. The glomerular microvasculature in the kidneys 
is particularly susceptible to injury through direct targeting of VEGF by antiangiogenic 
therapy. The common occurrence of proteinuria after inhibition of VEGF signaling reflects 
importance of VEGF in normal renal function. Patients on lucitanib should be monitored for 
proteinuria as specified in the relevant protocol. Management of treatment-emergent 
proteinuria is described in Section 8.A.6.5.2. 
Detailed information and Guidance for the Investigator is presented in the lucitanib IB.  
 Rationale for Rucaparib and Lucitanib Combination 
Treatment with a PARP inhibitor or the VEGF inhibitor, bevacizumab, has demonstrated 
benefit in the ovarian cancer setting.36,52-54 In addition, a Phase 2 clinical study in patients 
with recurrent ovarian cancer treated with the PARP inhibitor olaparib and the anti-
angiogenic agent cediranib has shown promise (see Section 8.A.3.2). The combination of a 
PARP inhibitor with a VEGF inhibitor, which have distinctly different mechanisms of action, 
have also shown synergistic effects in nonclinical studies (Clovis Oncology, data on file). In 
vitro, the ability of rucaparib in combination with lucitanib to inhibit tumor growth was 
evaluated using a triple negative breast cancer cell line (MDA-MB-436) harboring the 
BRCA1 gene mutation. All treatment groups demonstrated significant tumor inhibition 
(p < 0.0001), with the rucaparib plus lucitanib combination showing superior activity 


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compared to lucitanib (p = 0.0034) and rucaparib (p < 0.0001) alone (Clovis Oncology; data 
on file). 
Further, nonclinical data suggest that restriction of angiogenesis produces a hypoxic state that 
can subsequently induce a BRCA-like phenotype by decreasing BRCA1 and RAD51 
expression.55 Anti-angiogenesis therapies, including bevacizumab and cediranib, have been 
shown to induce a higher incidence of hypoxia and genetic instability, a reduction in HRR, 
and therefore, subsequent sensitivity to PARP inhibition42,56 The inhibition of VEGFR-3 also 
results in down-regulation of BRCA1 and BRCA2 expression and can restore 
chemosensitivity in ovarian cancer models.46 
PARP inhibitors have demonstrated robust clinical activity in patients with deleterious 
BRCA1/2-mutant ovarian cancer. However, in patients with ovarian cancer and BRCA wild-
type (BRCAwt) disease, targeted treatment options remain elusive with research ongoing to 
define the aberrations responsible for the disease and its progression. Standard 
chemotherapy, in the form of platinum-based doublet regimens, remains the primary choice 
of treatment for patients with ovarian cancer who are classified as platinum-sensitive 
(platinum-free interval [PFI] ≥ 6 months). For patients with platinum-resistant disease (PFI 
≥ 1 month to < 6 months), single-agent chemotherapy is standard, demonstrating only modest 
response rates. However, in the open-label, Phase 3 AURELIA study, the addition of 
bevacizumab to chemotherapy demonstrated significant improvement in PFS and the ORR in 
patients with platinum-resistant ovarian cancer.57 The median PFS doubled in the 
combination bevacizumab/chemotherapy group vs chemotherapy alone (6.7 vs 3.4 months; 
HR 0.48 [95% CI 0.38-0.60]; p < 0.001), and the ORR was reported as 27.3% in patients 
receiving bevacizumab/chemotherapy compared to 11.8% in patients receiving 
chemotherapy alone. The overall survival benefit was found to be not clinically significant 
between the groups. An increased incidence of hypertension, proteinuria, gastrointestinal 
perforation, and fistula/abscess was observed in the bevacizumab/chemotherapy arm 
compared to chemotherapy alone. A lower incidence of abdominal pain, vomiting, fatigue, 
and dyspnea were observed in the combination arm, while other toxicities, including 
hematologic toxicities consistent with the chemotherapy backbone, were generally similar 
across arms. Despite these encouraging results, other efficacious treatment options that may 
ameliorate the potential of cumulative toxicities from chemotherapy are needed for patients 
with platinum-resistant ovarian cancer. Based on nonclinical evidence of synergic activity 
and activity in ovarian cancer in combination studies of cediranib and olaparib (see 
Section 8.A.3.2), this study proposes to evaluate the hypothesis that an HRR state can be 
induced through treatment with antiangiogenic agent, which through use of a PARP inhibitor 
can induce synthetic lethality and tumor cell death. This Phase 1b/2 study will evaluate the 
safety, tolerability, and preliminary efficacy of rucaparib in combination with lucitanib in 
patients with an advanced/metastatic solid tumor or advanced gBRCAwt ovarian cancer. 
8.A.3.1 
Dose and Duration Rationale  
Expected constitutional symptoms of asthenia/fatigue and gastrointestinal associated 
toxicities, including nausea, diarrhea, vomiting, and abdominal pain, are potentially 
overlapping with a combination of lucitanib and rucaparib treatment (see Section 1.1.1.2.3 
and Section 8.A.2.3.3). Thus, the initial dose cohort (Dose Cohort 1) to be evaluated in 


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Phase 1b will consist of a rucaparib dose that is ~50% of the approved starting monotherapy 
dose (ie, 300 mg BID) and a lucitanib dose that is < 40% of the clinical dose used in Phase 2 
studies (ie, 4 mg QD). Doses of rucaparib and/or lucitanib less than 300 mg BID and 4 mg 
QD, respectively, may be evaluated based on unacceptable toxicities observed in Dose 
Cohort 1.   
8.A.3.2 
Expansion Cohorts Rationale 
PARP inhibitors in combination with anti-angiogenic agents have been well-studied in 
patients with breast and ovarian cancer. 
Liu et al (2014) have shown significant clinical benefit in a Phase 2 combination study in 
patients with gBRCA-mutated, platinum-sensitive, recurrent ovarian cancer treated with 
olaparib and cediranib. Cediranib is a potent, selective, orally bioavailable inhibitor of the 
tyrosine kinases VEGFR-1, VEGFR-2, and VEGFR-3 with additional activity observed 
against PDGFR and the proto-oncogene, c-kit. The median invPFS for the olaparib and 
cediranib combination was 17.7 months (95% CI, 14.7-not reached) compared to olaparib 
alone at 9.0 months (95% CI, 5.7-16.5) (HR 0.418 [95% CI, 0.229–0.763]; p = 0.005).9 The 
ORR was 79.6% with olaparib and cediranib (95% CI 1.53-12.22, p = 0.002) compared to 
47.8% with monotherapy olaparib. In the subset of patients with platinum-sensitive ovarian 
cancer, with gBRCAwt or unknown BRCA status (collective called BRCAwt/unk) disease, an 
improvement in PFS was also observed in patients receiving the combination of olaparib and 
cediranib (16.5 months; 95% CI, 1.8-inf) vs monotherapy olaparib (5.7 months; 95% CI, 5.3-
11.2) (HR 0.32; p = 0.008), and an increase in ORR of 76% vs 32%, respectively, was 
observed (p = 0.006). A greater incidence of Grade 3/4 AEs was observed in the combination 
arm compared to the monotherapy olaparib arm, including hypertension, fatigue, and 
diarrhea, with 77% of patients in the olaparib and cediranib arm requiring a dose reduction 
compared to 27% in the olaparib arm. 
In another Phase 1/2 study (ENGOT-OV24/AVANOVA1), the PARP inhibitor niraparib was 
evaluated in combination with bevacizumab in patients with platinum-sensitive recurrent 
ovarian cancer. In the Phase 1 portion of the study, 12 patients were enrolled into the 
single-arm study, where patients received combination bevacizumab (15 mg/kg in 21-day 
cycles) and niraparib (escalating doses of 100, 200, or 300 mg QD) in a 3+3 dose escalation 
design. The majority (75%) of the 12 patients enrolled in this dose escalation phase were 
gBRCAwt. In the Phase 1 portion of the study, an ORR of 45% (1 CR, 4 PRs), disease control 
rate of 91%, and median PFS of 49 weeks were reported.58 In the Phase 1 portion of the study 
a DLT of Grade 3 thrombocytopenia that persisted for ≥ 5 days was observed at the highest 
dose level (bevacizumab 15 mg/kg IV; niraparib 300 mg QD). Other common toxicities 
report in Cycle 1 included Grade 3 and 4 AEs of hypertension (42%), anemia (25%, and 
thrombocytopenia (8.3%). The Phase 2 portion of the study is ongoing and the primary 
endpoint of PFS has not been reported.  
 Treatment Arm A Study Design 
Treatment Arm A of this study will investigate the safety, tolerability, PK, and efficacy of the 
PARP inhibitor rucaparib in combination with the angiogenesis inhibitor lucitanib.  


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As described in Section 3.1, the treatment arm will consist of 2 phases: Phase 1b is a 
dose-escalation phase primarily to determine the MTD, if possible, and RP2D; and Phase 2 
investigates the RP2D for the combination of rucaparib and lucitanib in patients with 
prespecified tumor types. 
For patients enrolled into Treatment Arm A (Phase 1b or Phase 2) of the study, patients will 
receive rucaparib BID and lucitanib QD continuously in 28-day cycles. 
8.A.4.1 
Treatment Arm A Screening and Enrollment 
All patients will undergo screening assessments, including disease status per RECIST v1.1, 
prior to enrollment, within the time frame specified by the Schedule of Assessments 
(Table 8.A-7).  
Treatment Arm A will enroll patients who have met all of the inclusion criteria and none of 
the exclusion criteria presented in Section 8.A.5.2 and Section 8.A.5.3, respectively. The 
criteria may be different depending upon which phase of Treatment Arm A the patient is 
enrolled; these phase-specific criteria are indicated, as appropriate.  
Phase 1b will enroll patients with an advanced, recurrent, or metastatic solid tumor who have 
received at least 1 prior line of therapy in this setting. Provided all other eligibility criteria are 
met, patients with a deleterious gBRCA mutation are permitted to enroll into this Phase 1b 
portion of Treatment Arm A. 
Phase 2 will enroll patients into 1 of 2 cohorts:  
Cohort A1: 
Patients with platinum-sensitive, gBRCAwt, high-grade serous or 
Grade 2/Grade 3 endometrioid EOC, FTC, or PPC (collectively termed 
high-grade ovarian cancer [HGOC]) 
Cohort A2: 
Patients with platinum-resistant, gBRCAwt HGOC  
 
Patients enrolled into Cohort A1 or A2 (HGOC) will have received at least 1 prior line of 
platinum-based chemotherapy in the metastatic setting. Cohort A1 will enroll patients with 
platinum-sensitive disease, defined as disease progression ≥ 6 months after the most recent 
platinum-based chemotherapy, and Cohort A2 will enroll patients with platinum-resistant 
disease, defined as disease progression ≥ 1 to < 6 months after the most recent platinum-
based chemotherapy. In addition, Cohort A1 and Cohort A2 will exclude patients with a 
locally tested and confirmed deleterious gBRCA mutation (ie, patients will be gBRCAwt). 
8.A.4.2 
Treatment Arm A: Treatment Phase 
For both Phase 1b and Phase 2 of Treatment Arm A, patients will visit the study site on 
Day 1, Day 4, and Day 15 of Cycle 1; on Day 1 and Day 15 of Cycle 2, and on Day 1 of 
every cycle thereafter (see Table 8.A-7).  
Patients will be assessed for disease status per RECIST v1.1 every 8 calendar weeks 
(± 1 week) for the first 18 months following initiation of combination study treatment 


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(Cycle 1 Day 1), then every 16 weeks (± 1 week) thereafter until radiological disease 
progression as assessed by the investigator, death, loss to follow-up, withdrawal from study, 
or study termination, or initiation of subsequent anticancer treatments. Responses (CR or PR) 
must be confirmed with a scan no less than 4 weeks after initial response. 
8.A.4.2.1 
Phase 1b 
Phase 1b is based on a standard 3+3 design as described in Section 3.1.3.1. The first dose of 
combination study treatment (rucaparib and lucitanib) will be administered on Day 1 of 
Cycle 1; both drugs will be dosed continuously thereafter. The first 28 days of study 
treatment (Cycle 1) is the DLT-evaluation period. During the DLT-evaluation period, 
patients will visit the study site on Day 1, Day 4, and Day 15.  
The initial combination dose consists of oral rucaparib 300 mg BID and an oral lucitanib 
4 mg QD, with both drugs administered continuously. The dose of rucaparib will be escalated 
in 100-200 mg BID increments up to a maximum of 600 mg BID. The dose of lucitanib will 
be escalated in 2 mg QD increments up to a maximum of 10 mg QD. Once the initial dose 
has been evaluated for the first cohort and deemed safe and tolerable, parallel cohorts, where 
the dose of 1 investigational agent remains the same as in the prior cohort while the dose of 
the other agent is escalated, may be evaluated going forward. For example, a cohort receiving 
400 mg BID rucaparib in combination with 4 mg QD lucitanib may be evaluated in parallel 
with a separate cohort receiving 300 mg BID rucaparib in combination with 6 mg QD 
lucitanib. Doses of rucaparib and/or lucitanib less than 300 mg BID and 4 mg QD, 
respectively, may be evaluated based on unacceptable toxicity observed at the initial dose 
cohort.  
Prior to initiating treatment at each new combined dose level or prior to expanding an 
existing dose level, a safety teleconference will be held to review patient data, including but 
not limited to demographics, PK results (if available), study drug combination dosing, 
concomitant medications, hematology and chemistry, and AEs, and then confer and 
document agreement that dose escalation and/or expanding an existing dose level is/are 
considered appropriately safe. Safety teleconferences will include study investigators, the 
sponsor’s medical monitor, and may include other representatives or designees of the sponsor 
and the study sites. 
Dose modifications will be made based on clinical judgement and the dose modification 
guidance in Section 8.A.6.4. 
8.A.4.2.1.1 
Dose-limiting Toxicity Criteria 
A DLT considered for dose escalation in Phase 1b of Treatment Arm A is defined as any of 
the following occurring within the first 28 days of initiating combination treatment (Cycle 1) 
that is assessed by the investigator as possibly related to rucaparib and/or lucitanib (refer to 
Section 10.7.4 for consideration of causal relationship). Where applicable, the event will be 
assessed, according to NCI CTCAE v5.0. 


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• Grade 3 or greater febrile neutropenia (ie, fever > 38.3°C with ANC < 1.0 × 109/L) of any 
duration; 
• Grade 3 or 4 neutropenia lasting more than 7 days despite granulocyte colony-stimulating 
factor (GCSF) administration; 
• Grade 3 thrombocytopenia (platelets < 50 × 109/L) with significant bleeding or Grade 4 
thrombocytopenia (platelets < 25 × 109/L) ≥ 5 days duration; 
• Grade 4 anemia (ie, life-threatening consequences; urgent intervention indicated) or any 
anemia (regardless of grade or severity) requiring a blood transfusion; 
• Hypertension, defined as systolic blood pressure [SBP] ≥ 160 mmHg and/or diastolic 
blood pressure [DBP] ≥ 100 mmHg, that does not resolve to ≤ Grade 2 within 14 days 
despite optimized antihypertensive therapy, or any Grade 4 hypertension (hypertension 
with life-threatening consequences); 
• Grade 3 or greater hyponatremia lasting more than 5 days despite repletion; 
• Any nonhematological AE ≥ Grade 3, with the exception of: 
- 
Nausea, vomiting, and diarrhea well controlled by systemic medication and with 
duration ≤ 48 hours; 
- 
Fatigue; 
- 
Grade 3 ALT or AST not accompanied by concomitant increase in total bilirubin 
above the upper limit of normal (ULN). Note: any Grade 4 ALT/AST is a DLT. 
 
If a patient is not evaluable for a DLT, then an additional patient may be enrolled. For the 
definition of evaluability, please refer to Section 9.2.  
8.A.4.2.1.2 
RP2D Selection and Expansion 
As described in Section 3.1.3.1.2, once the RP2D of the combination has been provisionally 
established, up to 10 additional patients may be enrolled and treated in Phase 1b, in order to 
further characterize safety, tolerability, and PK and confirm that this is the optimal dose 
combination to evaluate in the Phase 2 portion. 
8.A.4.2.1.3 
Phase 1b – Cycle 2 and Beyond 
Following the DLT-evaluation period, patients will come into the study site for a visit on 
Day 1 and Day 15 of Cycle 2, and on Day 1 of every cycle thereafter. Patients will be 
monitored for safety, PK, and efficacy as outlined in the Schedule of Assessments 
(Table 8.A-7) and PK Assessments (Table 8.A-8). 
After the 28-day DLT-evaluation period, recommendations for rucaparib and lucitanib dose 
modification for the management of specific AEs are provided in Section 8.A.6.4 and 
Section 8.A.6.5, respectively. 
Patients tolerating the investigational treatment(s) at the assigned dose combination for at 
least 4 cycles may be permitted to escalate to the next highest combination dose regimen as 


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long as the new dose regimen is lower than that being currently evaluated for safety and 
tolerability and/or the dose level is the same or lower than that determined to be the RP2D. 
All individual patient dose-escalation steps must be approved by the study’s medical 
monitor. 
Patients will be treated until disease progression, unacceptable toxicity, patient or 
investigator request to discontinue, death, initiation of any other anticancer therapy, positive 
pregnancy test, or termination of the study (Section 3.2). If a patient receiving study drug has 
met criteria for radiologic disease progression by RECIST v1.1 criteria but continues to 
derive clinical benefit per the investigator, continuation of treatment may be permitted after 
discussion with the medical monitor (Section 5.9).  
8.A.4.2.2 
Phase 2 Cohorts 
Upon determination of the RP2D from Phase 1b, Phase 2 will be initiated. In Phase 2, the 
selected RP2D from Phase 1b will be evaluated using Simon 2-stage designs in separate and 
parallel cohorts (see Section 8.A.9.1). Patients meeting all eligibility criteria will be enrolled 
into 1 of 2 cohorts as follows: 
Cohort A1: 
Patients with platinum-sensitive, gBRCAwt HGOC 
Cohort A2: 
Patients with platinum-resistant, gBRCAwt HGOC 
 
The Phase 2 cohorts were chosen due to the potential susceptibility to the combination of 
rucaparib and lucitanib (Section 8.A.3.2).  
The RP2D of the combination of rucaparib and lucitanib may be further adjusted, and/or 
alternative dosing schedules assessed during Phase 2 based on emerging safety, PK, and 
efficacy data.  
Patients will be monitored for safety, PK, and efficacy as outlined in the Schedule of 
Assessments (Table 8.A-7) and PK Assessments (Table 8.A-8). 
Dose modification and AE management guidelines in Section 8.A.6.4 and Section 8.A.6.5, 
respectively, should be followed throughout the Phase 2.  
Patients will be treated until disease progression, unacceptable toxicity, patient or 
investigator request to discontinue, death, initiation of any other anticancer therapy, positive 
pregnancy test, or termination of the study (Section 3.2). If a patient receiving study drug has 
met criteria for radiologic disease progression by RECIST v1.1 criteria but continues to 
derive clinical benefit per the investigator, continuation of treatment may be permitted after 
discussion with the medical monitor (Section 5.9).  
8.A.4.3 
End of Treatment Arm A (both Phases) and Safety Follow-up 
Upon treatment discontinuation, regardless of reason (with the exception of withdrawal of 
consent or death), patients will have an End of Treatment Visit, and assessments are specified 
for each treatment arm in the Schedule of Assessments within Table 8.A-7. All patients will 


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be followed for at least 28 days after the last dose of study drug. Safety follow-up 
assessments are specified for Treatment Arm A in the Schedule of Assessment. 
 Study Population Selection for Treatment Arm A 
8.A.5.1 
Treatment Arm A: Number of Patients and Sites 
In Phase 1b, it is estimated that up to 55 patients with advanced or metastatic solid tumors 
will be enrolled, dependent upon the number of dose cohorts enrolled.  
In Phase 2, up to 80 patients will be enrolled into the following cohorts:  
Cohort A1:  Up to 49 patients with platinum-sensitive, gBRCAwt HGOC 
Cohort A2:  Up to 31 patients with platinum-resistant, gBRCAwt HGOC 
 
Patients will enroll into either Phase 1b or Phase 2, but a patient cannot enroll into both 
phases of the same treatment arm. For Phase 2, patients will enroll simultaneously across 
both cohorts based on separate Simon 2-stage designs for each cohort. Enrollment into 
Phase 2 for each cohort will continue until the required number of patients for each stage is 
reached (Section 8.A.9.1). 
The enrollment of the 2 phases in Treatment Arm A of the study is up to 135 patients. It is 
planned that 3 to 6 sites in the US are expected to participate in Phase 1b of the study; 
approximately 25 sites globally may be activated to participate in the Phase 2 portion of the 
study. 
8.A.5.2 
Treatment Arm A: Inclusion Criteria 
All patients participating in Treatment Arm A must meet all of the following inclusion 
criteria: 
1. Have signed an Institutional Review Board (IRB)/ IEC-approved informed consent form 
(ICF) prior to any study-specific evaluation; 
2. Be ≥ 18 years of age at the time the ICF is signed;  
3. Have an ECOG performance status of 0 or 1; 
4. Have a life expectancy greater than 3 months per investigator discretion; 
5. Have adequate organ function confirmed by the following laboratory values obtained 
within 14 days prior to first dose of study drug: 
a. Bone Marrow Function: 
i. 
ANC ≥ 1.5 × 109/L; 
ii. 
Platelets > 100 × 109/L; 
iii. 
Hemoglobin ≥ 9 g/dL 
Note: All hematology values must be achieved without the need for transfusion or 
growth factors ≤ 14 days prior to the planned start of study treatment (C1D1); 


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b. Hepatic Function 
i. 
AST and ALT ≤ 3 × institutional ULN; if liver metastases, then ≤ 5 × the 
institutional ULN; 
ii. 
Total bilirubin ≤ 1.5 × institutional ULN; 
iii. 
Albumin ≥ 30 g/L (3.0 g/dL); 
c. Renal Function 
i. 
Creatinine ≤ 1.5 × institutional ULN OR estimated glomerular filtration rate 
(eGFR) ≥ 45 mL/min using the Cockcroft-Gault formula (Appendix 1); 
ii. 
Less than or equal to 1+ proteinuria. Patients with > 1+ proteinuria on dipstick 
must perform a 24-hour urine collection demonstrating ≤ 1.0 g over 24 hours; 
6. Have left ventricular ejection fraction (LVEF) ≥ 50% by echocardiogram (ECHO) or 
multiple-gated acquisition (MUGA) scan evaluation performed during screening using 
institutional standard; 
7. Have measurable disease per RECIST v1.1; 
8. Women of childbearing potential must have a negative serum or plasma pregnancy test 
within 3 days prior to administration of the first doses of study drug; 
9. Have sufficient archival or more recently obtained FFPE tumor tissue available for 
genomic analysis (refer to Section 7.5.1); 
10. Phase 1b: Have a histologically or cytologically confirmed diagnosis of locally 
advanced, recurrent, or metastatic solid tumor; 
11. Phase 1b: Received at least 1 prior line of therapy in the locally advanced, recurrent, or 
metastatic setting and have progressed on standard therapy. Patients with ovarian cancer 
associated with a deleterious BRCA1/2 mutation must have received prior treatment with 
a PARP inhibitor. 
12. Phase 2: Criteria Specific to the expansion cohorts 
a. Have a histologically confirmed diagnosis of high-grade serous or Grade 2 or Grade 3 
endometrioid EOC, FTC, or PPC; 
b. Received ≥ 1 prior line of platinum-based chemotherapy and have relapsed or 
progressive disease (PD) as confirmed by radiologic assessment; 
c. Had documented treatment-free interval of ≥ 6 months following the first 
chemotherapy regimen received; 
d. COHORT A1: Have platinum-sensitive disease, defined as disease progression 
≥ 6 months after last dose of platinum-based chemotherapy; or 
e. COHORT A2: Have platinum-resistant disease, defined as disease progression ≥ 1 to 
< 6 months after last dose of platinum-based chemotherapy; 
f. Have gBRCAwt ovarian cancer (ie, patients with a deleterious germline mutation in 
BRCA1 or BRCA2, as determined by a local laboratory that has received an 
international or country-specific quality standards certification, are excluded). 
 


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8.A.5.3 
Treatment Arm A Exclusion Criteria 
Patients who meet any of the following criteria will be excluded from Treatment Arm A: 
1. Unable to swallow oral study drug; 
2. Have an active second malignancy, ie, patient known to have potentially fatal cancer 
present for which he/she may be (but not necessarily) currently receiving treatment.  
Note: Patients with a history of malignancy that has been successfully treated, with no 
evidence of active cancer for 3 years prior to enrollment, or patients with surgically-
cured, low-risk tumors, such as early stage cervical or endometrial cancer are allowed to 
enroll. Patients receiving anticancer hormonal therapy in the maintenance setting are 
allowed to enroll.  
3. Phase 2 only: Have received prior treatment with a PARP inhibitor;  
Note: patients in Phase 1b may have received a prior PARP inhibitor as long it was not 
the most recent treatment received; 
4. Have received prior treatment with an anti-angiogenesis inhibitor(s), with the exception 
of bevacizumab in combination with chemotherapy and/or as maintenance to treat newly 
diagnosed disease in the frontline setting; 
5. Phase 2 only: Have platinum-refractory disease, defined as disease that progressed by 
radiologic assessment during or within 4 weeks after completing the last dose of the most 
recent platinum-based therapy; 
6. Have a known history of MDS; 
7. Have symptomatic and/or untreated central nervous system (CNS) metastases. Patients 
with asymptomatic, previously-treated CNS metastases are eligible provided they have 
been clinically stable (not requiring steroids for at least 8 weeks prior to first dose of 
study drug) and have had appropriate scans at the screening assessment; 
8. Have pre-existing duodenal stent and/or any gastrointestinal disorder or defect that 
would, in the opinion of the investigator, interfere with absorption of study drug; 
9. Have known human immunodeficiency virus (HIV) or acquired immunodeficiency 
syndrome (AIDS)-related illness, or history of chronic hepatitis B or C, with the 
exception of patients with sustained virologic response after completion of treatment for 
hepatitis C; 
10. Have received chemotherapy, radiation, antibody therapy, or other immunotherapy, gene 
therapy, vaccine therapy, or experimental drugs ≤ 14 days prior to first scheduled dose of 
study drugs;  
11. Have ongoing toxicity from prior cancer treatment ≥ Grade 2 by NCI CTCAE v5.0, 
except alopecia; additionally, ongoing Grade 2 peripheral neuropathy may be permitted 
with prior advanced approval from the sponsor; 
12. Have had a nonstudy related minor surgical procedure ≤ 5 days, or major surgical 
procedure ≤ 21 days, prior to first dose of study drug. In all cases, the patient must be 
sufficiently recovered and stable before treatment administration; 


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13. Have had a hospitalization for bowel obstruction within 3 months prior to enrollment;  
14. Have a history of gastrointestinal or genitourinary fistula, gastrointestinal perforation, or 
intra-abdominal abscess, unless previously resected, and confirmed to be fully healed 
with no evidence of recurrence; 
15. History of major thromboembolic event, defined as: 
a. Uncontrolled pulmonary embolism (PE); 
b. Deep venous thrombosis (DVT); 
c. Other related conditions, with exception of patients with stable therapeutic 
anticoagulation for PE or DVT > 3 months prior to enrollment; 
16. Have a history of hemoptysis, clinically significant hemorrhage or history of cerebral 
vascular accident, transient ischemic attack or subarachnoid hemorrhage within 3 months 
prior to enrollment; 
17. Have clinically relevant cardiac arrhythmia, unstable angina or myocardial infarction 
within 6 months prior to enrollment; congestive heart failure greater than New York 
Heart Association (NYHA) III, severe peripheral vascular disease, QTcF > 450 msec; or 
clinically significant pericardial effusion; 
18. Have the need for ongoing concomitant administration of strong inhibitors of CYP2C8 or 
CYP3A4 or strong inducers of CYP3A4 ≤ 7 days prior to first dose of study drug or have 
on-going requirements for these medications (Appendix 2); 
19. Have radiographic evidence of cavitation or necrotic tumors with invasion of adjacent 
major blood vessels; 
20. Have unstable or uncontrolled BP defined as SBP ≥ 140 mmHg and/or DBP ≥ 90 mmHg 
despite optimized anti-hypertensive therapy per investigator judgement, or history of 
hypertensive crisis. Patients must be willing and able to check and record daily BP 
readings; 
21. Have uncontrolled hypothyroidism defined as thyroid stimulating hormone (TSH) 
> 5 mIU/mL while receiving optimized thyroid hormone replacement therapy; 
22. For female patients of childbearing potential and all male patients, the following are 
exclusion criteria, as applicable: 
a. Refusal to use highly effective method of contraception or to practice true abstinence 
during treatment and for 6 months after the last dose of rucaparib study treatment. 
b. Pregnant or breast feeding.  
c. Women of childbearing potential must not be considering getting pregnant during the 
study and for 6 months following the last dose of study drug. 
d. Male patients who refuse to use condoms during sex during and up to 6 months after 
study treatment. Male patients must not make semen donations during treatment and 
for 6 months following the last dose of rucaparib. 
23. Have any other condition that may increase the risk associated with study participation or 
may interfere with the interpretation of study results, and, in the opinion of the 
investigator, would make the patient inappropriate for entry into the study. 


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No waivers of these inclusion or exclusion criteria will be granted by the investigators, the 
sponsor, or its designee. 
8.A.5.4 
Patients or Partners of Patients of Reproductive Potential 
Refer to Section 4.1. 
 Study Treatment(s): Treatment Arm A 
Refer to Section 5 for rucaparib treatment. 
8.A.6.1 
Investigational Drug Product – Lucitanib 
Lucitanib (also named S 80881, CO-3810, and E-3810) is an oral formulation. Lucitanib 
tablets for oral administration will be supplied to the study sites by the sponsor. A brief 
description of lucitanib is provided below with details in the Pharmacy Manual. 
Table 8.A-1 Description of Lucitanib 
Drug Name 
Lucitanib; S 80881, CO-3810, and E-3810 
INN 
Lucitanib 
Formulation 
(strengths expressed as 
free base) 
Lucitanib (free base) is formulated as film coated immediate release 
tablets for oral dosing. 
Tablets are available in strengths of 1 mg (salmon, round), 2 mg 
(yellow, round), and 5 mg (white, round).  
How Supplied 
1 mg, 2 mg, and 5 mg (as free base) strength tablets in 30 count 
bottles. Patients may receive one or more strengths. 
Storage Conditions 
Tablets should be stored between 15-30°C (59-86°F). 
 
8.A.6.2 
Lucitanib Packaging and Labeling 
Lucitanib tablets are packaged in 30-count HDPE bottles with a child resistant closure and 
should be stored between 15°C and 30°C (59°F to 86°F). Patients will be dispensed one or 
more strengths of each study drug depending on their current doses of the study drug 
combination. The number of bottles of each strength dispensed will be sufficient to supply 
28 days treatment per cycle, including a small overage. 
8.A.6.3 
Preparation and Administration of Lucitanib 
Lucitanib is administered QD. Tablets should be swallowed with water (240 mL or 8 oz) at 
approximately the same time each day, on an empty stomach (abstain from food 2 hours 
before and 1 hour after dosing). Lucitanib may be provided as 1 mg, 2 mg, and 5 mg dose 
strength tablets, as described in Table 8.A-1. 
The morning doses of rucaparib and lucitanib, ideally, should be taken at the same time; due 
to the food restriction for lucitanib dosing, administration should be on an empty stomach, as 


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stated above. There are no strict requirements regarding the order in which rucaparib and 
lucitanib should be ingested by the patient; however, on PK days, the 2 medications should 
be dosed as closely together as possible for convenient PK sampling.  
The evening dose of rucaparib can be taken with or without food. 
8.A.6.4 
Dose Modification and Retreatment Criteria for Rucaparib and Lucitanib 
Toxicities should be managed with supportive care and with dose modification for each of 
the study drugs according to the attribution of causality for the toxicity based on investigator 
judgement and consultation with the sponsor, as appropriate. A dose modification of 
rucaparib or lucitanib is permitted, with the other dose remaining constant, if the causality is 
believed to be related to 1 study drug, but not the other. General management of AEs are 
described for the rucaparib and lucitanib combination in Table 8.A-2. Management of new or 
worsening pulmonary symptoms is described in Section 8.A.6.4.1. Management of AEs 
specific to lucitanib is provided in the following sections and supersedes the dose 
modifications described in the table below: 
• Hypertension – see Section 8.A.6.5.1 
• Proteinuria – see Section 8.A.6.5.2 
• Hypothyroidism – see Section 8.A.6.5.3  
• Decrease in LVEF – see Section 8.A.6.5.4 
• Posterior Reversible Encephalopathy Syndrome (PRES) – see Section 8.A.6.5.5 
 
At the discretion of the investigator, the dose of rucaparib and/or lucitanib may be held 
and/or reduced for Grade 2 toxicity that is attributed to either rucaparib or lucitanib alone, or 
in combination, and not adequately controlled by concomitant medications and/or supportive 
care. 
If any blood parameters remain clinically abnormal after 3 weeks of dose interruption, the 
patient should be referred for further evaluation, as clinically appropriate. For clinically 
significant hematology results, bone marrow analysis and/or blood cytogenetic analysis 
should be considered according to standard hematological practice. 
If a patient continues to experience the same toxicity despite multiple dose reduction steps to 
the lowest allowable dose, or if dosing with either study drug is interrupted for 
> 21 consecutive days due to the toxicity, study treatment should be discontinued 
(Section 8.A.6.4.3), unless otherwise agreed upon between the investigator and the sponsor; 
exceptions are noted in Section 8.A.6.5 (Management of Adverse Events Specific to 
Lucitanib).  


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Table 8.A-2 Rucaparib and Lucitanib Dose Modification Criteria and Action Taken 
Adverse Event including 
Laboratory Abnormalities 
Severity 
(CTCAE 
Grade) 
Rucaparib 
Lucitanib 
Treatment 
Interruption 
Re-treatment 
Dose 
Modification 
Treatment 
Interruption 
Re-treatment 
Dose 
Modification 
Non-hematological Events 
Adverse event or laboratory 
abnormality 
1 or 2 
Nonea 
N/A 
Nonea 
Nonea 
N/A 
Nonea 
Adverse eventb 
3 or 4 
Hold dose 
≤ Grade 2 
1st occurrence: 
Same dosea 
2nd occurrence 
of same AE: 
Reduce dosec  
3rd occurrence 
of same AE: 
Discontinue 
Hold dose 
≤ Grade 2 
1st occurrence: 
Same dosea 
2nd occurrence 
of same AE: 
Reduce dosec  
3rd occurrence 
of same AE: 
Discontinue 
ALT/AST elevation 
(in the absence of other signs 
of liver dysfunction) 
3 
Continuation of 
dosing permitted 
provided total 
bilirubin is 
< ULN and ALP 
is < 3 x ULN; 
monitor LFTs 
weekly; 
Hold if levels do 
not decline 
within 2 weeks 
or if levels 
increase 
≤ Grade 2 
1st occurrence: 
Same dosea 
 
2nd occurrence 
of same AE: 
Reduce dosec 
3rd occurrence 
of same AE: 
Discontinue 
Continuation of 
dosing permitted 
provided total 
bilirubin is 
< ULN and ALP 
is < 3 x ULN; 
monitor LFTs 
weekly; 
Hold if levels do 
not decline 
within 2 weeks 
or if levels 
increase 
≤ Grade 2 
1st occurrence: 
Same dosea 
 
2nd occurrence 
of same AE: 
Reduce dosec 
3rd occurrence 
of same AE: 
Discontinue 
ALT/AST elevation 
4 
Hold;  
monitor LFTs 
weekly; 
≤ Grade 2 
Reduce dosec 
Monitor LFTs 
weekly for 
3 weeks after 
restart of study 
Hold dose; 
monitor LFTs 
weekly; 
≤ Grade 2 
Reduce dosec 
Monitor LFTs 
weekly for 
3 weeks after 
restart of study 


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Table 8.A-2 Rucaparib and Lucitanib Dose Modification Criteria and Action Taken 
drug 
drug 
Adverse Event including 
Laboratory Abnormalities 
Severity 
(CTCAE 
Grade) 
Rucaparib 
Lucitanib 
Treatment 
Interruption 
Re-treatment 
Dose 
Modification 
Treatment 
Interruption 
Re-treatment 
Dose 
Modification 
ALT or AST elevations 
(> 3 × ULN)  
AND  
total bilirubin elevation 
(> 2 × ULN) - suspected 
DILI [Section 10.9]23,24 
NA 
Holdd; 
monitor LFTs 
weekly 
≤ Grade 1 
(or baseline) 
Subject to 
investigation: 
reduce dosec 
If DILI is 
confirmed, 
treatment should 
be permanently 
discontinued 
Holdd; 
monitor LFTs 
weekly 
≤ Grade 1 
(or baseline) 
Subject to 
investigation: 
reduce dosec 
If DILI is 
confirmed, 
treatment should 
be permanently 
discontinued  
Hematological Events 
Adverse event or laboratory 
abnormality 
1 or 2 
Nonea 
N/A 
Nonea 
Nonea 
N/A 
Nonea 
Adverse event or laboratory 
abnormality 
3 or 4 
Hold dose 
≤ Grade 2 
1st occurrence: 
Same dosea 
 
2nd occurrence 
of same AE: 
Reduce dosec 
3rd occurrence 
of same AE: 
Discontinue 
Hold dose 
≤ Grade 2 
1st occurrence: 
Same dosea 
 
2nd occurrence 
of same AE: 
Reduce dosec 
3rd occurrence 
of same AE: 
Discontinue 
Anemia 
≥ 3 
Hold dosee. 
≤ Grade 2 
Same or reduced 
dosea, c 
Hold dosee. 
≤ Grade 2 
Same or reduced 
dosea, c 
 
Abbreviations: AE = adverse event; ALP = alkaline phosphatase; ALT = alanine aminotransferase; AML = acute myeloid leukemia; ANC = absolute 
neutrophil count; AST = aspartate aminotransferase; BID = twice a day; BUN = Blood urea nitrogen; CTCAE = Common Terminology Criteria for 
Adverse Events; INR = international normalized ratio; LFT = liver function test; N/A = not applicable; ULN = upper limit of institutional normal 
a 
At the discretion of the investigator, the dose of rucaparib and/or lucitanib may be held and/or reduced for Grade 2 toxicity that is attributed to either 


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rucaparib or lucitanib alone, or in combination, and not adequately controlled by concomitant medications and/or supportive care. 
b 
Exceptions include Grade 3 or 4 nausea, vomiting, or diarrhea adequately controlled with systemic antiemetic/antidiarrheal medication administered in 
standard doses according to institutional guidelines; for management of hypertension, proteinuria, hypothyroidism, decrease in LVEF, or PRES refer to 
Section 8.A.6.4. 
c 
For dose reductions see Table 8.A-3. 
d 
Evaluate patient for the presence of confounding factors, including malignant disease in the liver, co-administration of other suspect drugs, cholestasis, and 
viral or autoimmune hepatitis, that could have caused the laboratory abnormalities. Other laboratory investigations of liver function such as INR should be 
implemented as indicated. If no alternative cause is identified, study drugs must be permanently discontinued. Patients should be followed until all 
abnormalities have returned to normal, returned to baseline levels, or an alternative cause is found to explain the combination of the increased 
transaminases and total bilirubin. 
e 
If anemia CTCAE Grade ≥3 persists for > 14 consecutive days, or a dependence upon blood transfusions occurs, then weekly complete blood counts 
should be performed until resolution of the event. If after 42 days of interruption and anemia has not improved to CTCAE Grade ≤ 1, the patient should be 
referred to hematologist and analysis of the bone marrow with cytogenetic studies and recommended according to standard practice. Bone marrow analysis 
should include a bone marrow aspirate (for cellular morphology, cytogenetic analysis, and flow cytometry) and a core biopsy (for bone marrow 
cellularity). 
 


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8.A.6.4.1 
Management of New or Worsening Pulmonary Symptoms 
If new or worsening unexplained pulmonary symptoms suggestive of pneumonitis 
(including, but not limited to, dyspnea) occur, or a deterioration of pulmonary function is 
observed, and/or radiologic abnormality is detected in the lungs, and this occurs in the 
absence of any clear diagnosis, a diagnostic workup (including high resolution CT scan) in 
consultation with a pulmonologist should be performed in order to rule out pneumonitis. 
During this time, treatment with rucaparib may be interrupted or continued per investigator 
discretion. Lucitanib treatment may also be interrupted or continued per investigator 
discretion. The contribution of lucitanib should be assessed independently. 
Following investigation, if pneumonitis is not confirmed, treatment may be 
resumed/continued as deemed appropriate by the investigator and in accordance with the 
study protocol directions for management of AEs. All confirmed events of pneumonitis 
should be treated as appropriate per medical judgement and institutional guidelines. If the 
event resolves and retreatment is being considered, please consult the study medical monitor. 
Retreatment may be resumed at the current or a reduced dose, if appropriate.  
Refer to Section 10.7 and Section 10.8 of the protocol for additional information regarding 
classification and reporting of pneumonitis (and similar events, ie, interstitial lung disease, 
pulmonary fibrosis, acute interstitial pneumonitis, alveolitis necrotizing, alveolitis, 
hypersensitivity pneumonitis, and organizing pneumonia) as an AESI. 
8.A.6.4.2 
Rucaparib and/or Lucitanib Dose Reductions 
Potential dose reduction steps for rucaparib and lucitanib based on different current doses are 
shown in Table 8.A-3. Rucaparib and lucitanib dose reductions will occur in step-wise 
sequence. Doses lower than rucaparib 300 mg BID are not permitted without consultation 
with the medical monitor, and doses lower than lucitanib 2 mg QD are not permitted. 
Unless otherwise specified, dose re-escalation upon resolution of the toxicity to < Grade 1 is 
permitted upon agreement between the investigator and sponsor. 
Table 8.A-3 Rucaparib and Lucitanib Dose Reductions 
Rucaparib 
Lucitanib 
Current Dosage 
Dose Reductiona 
Current Dosage 
Dose Reductiona 
600 mg BID 
500 mg BID 
10 mg QD 
8 mg QD 
500 mg BID 
400 mg BID 
8 mg QD 
6 mg QD 
400 mg BID 
300 mg BID 
6 mg QD 
4 mg QD 
300 mg BID 
200 mg BIDb 
4 mg QD 
2 mg QD 
- 
- 
2 mg QD 
None permitted 
Abbreviations: BID = twice a day; QD = once a day. 


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Table 8.A-3 Rucaparib and Lucitanib Dose Reductions 
Rucaparib 
Lucitanib 
Current Dosage 
Dose Reductiona 
Current Dosage 
Dose Reductiona 
a 
No more than 2 dose reductions for the same AE are allowed for either study drug, after which treatment 
with both study drugs will be discontinued. 
b 
Consult with sponsor’s medical monitor before reducing the dose of rucaparib to this level. 
 
8.A.6.4.3 
Rucaparib and/or Lucitanib Discontinuation 
Rucaparib and/or lucitanib should be permanently discontinued for any of the following: 
• If a patient continues to experience toxicity despite dose reduction steps to the lowest 
permissible dose for either study drug (see Table 8.A-3) or if dosing with either study 
drug is interrupted for > 21 consecutive days due to toxicity, treatment with both study 
drugs should be discontinued, with the following exceptions: 
- 
Treatment interruption > 21 days may be allowed if approved by the sponsor. Prior to 
re-initiating treatment for a patient with a treatment interruption lasting > 21 days, the 
study medical monitor/designee must be consulted. Tumor assessments should 
continue as per protocol even if treatment is interrupted. 
• Confirmed diagnosis of MDS/AML; 
• Any AE, laboratory abnormality, or intercurrent illness which, in the judgment of the 
investigator, presents a substantial clinical risk to the patient with continued oral study 
treatment dosing; or 
• Patient with progressive disease. If a patient receiving study drug has met criteria for 
radiologic disease progression by RECIST v1.1 criteria, but continues to derive clinical 
benefit per the investigator, continuation of treatment may be permitted after discussion 
with the sponsor (Section 5.9). 
 
8.A.6.5 
Management of Adverse Events Specific to Lucitanib 
8.A.6.5.1 
Management of Treatment-emergent Hypertension 
Patients with unstable or uncontrolled hypertension (defined as SBP ≥ 140 mmHg and/or 
DBP ≥ 90 mmHg despite optimized anti-hypertensive therapy per investigator judgement), or 
have a history of hypertensive crisis are excluded from this rucaparib and lucitanib 
combination arm (Exclusion Criteria #20). 
Pharmacological management of hypertension should be based on the investigator’s 
judgment, and no definite recommendations for an anti-hypertensive agent can be made. 
However, calcium channel blockers may be preferred as initial treatment based on their rapid 
action and safety profile. Angiotensin Converting Enzyme (ACE) inhibitors can be 
considered in case of concomitant proteinuria. In case of rapid elevation of BP, 
2 antihypertensive agents should be considered. The use of 3 antihypertensive agents, such as 


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concomitant use of a renin-angiotensin system inhibitor, calcium channel blocker, and a 
diuretic drug may be considered based on the investigator’s decision. In that case, close 
surveillance of kidney function and electrolytes is strongly recommended.  
Cardiologist and nephrologist advice should be sought when appropriate and especially in the 
context of hypertension associated AEs such as proteinuria.  
Abnormal BP measurements in the clinic should be repeated within an hour to confirm 
findings and assess clinical significance. Additionally, patients should be instructed to self-
measure and record their BP at home in a diary log at least 2 times per week while receiving 
lucitanib treatment. The patient must be educated before the first intake of study drug on the 
importance of BP self-monitoring, trained to recognize signs of hypertension, and trained on 
the importance of contacting the site if BP is greater than 160/100 mmHg at any time. 
Patient-monitored BP should be followed by the investigator at all clinic visits to evaluate the 
effectiveness of any concomitant anti-hypertensive treatment. 
For purposes of medical history reporting and AE reporting, it is important to follow the NCI 
CTCAE grading scale, taking into account not only the BP levels, but also the number of 
anti-hypertensive therapies (Table 8.A-4). 
In the case of lucitanib withdrawal, the patient’s BP must be monitored in order to adjust and 
progressively discontinue concomitant anti-hypertensive treatments that were started during 
the study. 
 
 
Table 8.A-4  NCI CTCAE Grading Scale for Hypertension 
Grade 1 
Prehypertension (SBP 120−139 mmHg or DBP 80−89 mmHg) 
Grade 2 
Stage 1 hypertension (SBP 140−159 mmHg or DBP 90−99 mmHg); medical 
intervention indicated; recurrent or persistent (≥ 24 hrs); symptomatic increase by 
> 20 mmHg (DBP) or to > 140/90 mmHg if previously within normal limits; 
monotherapy indicated 
Grade 3 
Stage 2 hypertension (SBP ≥ 160 mmHg or DBP ≥ 100 mmHg); medical intervention 
indicated; more than one drug or more intensive therapy than previously used indicated 
Grade 4 
Life-threatening consequences (eg, malignant hypertension, transient or permanent 
neurologic deficit, hypertensive crisis); urgent intervention indicated  
Grade 5 
Death 
Source:  NCI CTCAE, v5.0. 
Abbreviations: DBP = diastolic blood pressure; hrs = hours; SBP = systolic blood pressure. 


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First-time Hypertension 
If a patient experiences hypertension for the first time after starting the rucaparib and 
lucitanib combination, the following actions should be taken: 
• Initiate anti-hypertensive therapy immediately.   
• Immediate use of 2 anti-hypertensive agents can be considered in case of rapid 
elevation of BP. The antihypertensive agent can be adjusted over a period of 14 days. 
The patient should be followed by the investigator at least once per week to evaluate 
the response to anti-hypertensive treatment. During this period, interruption of 
lucitanib or dose modification is not necessary.  
• If BP decreases to < 140/90 mmHg within 14 days, continue lucitanib at the same 
dose. 
 
Previously-controlled Hypertension Worsens to Grade 2 
If a patient with previously-controlled hypertension experiences worsening in BP values after 
starting the rucaparib and lucitanib combination, with SBP from 140 to 159 mmHg and/or 
DBP from 90 to 99 mmHg, the following actions should be taken: 
• Review all current antihypertensive treatment and intensify/ adapt as needed. 
Immediate dose and therapeutic class optimization should be performed. Up to 3 
anti-hypertensive agents may be considered. 
• The anti-hypertensive agent can be adjusted over a period of 14 days. The patient 
should be followed by the investigator at least once per week to evaluate the response 
to anti-hypertensive treatment. During this period, interruption of lucitanib or dose 
modification is not necessary.  
• If BP decreases to < 140/ 90 mmHg within 14 days, continue lucitanib at the same 
dose and maintain anti-hypertensive treatment, as appropriate. 
 
Persistent Grade 2 Hypertension Despite Optimized Treatment 
If after starting the rucaparib and lucitanib combination, a patient has persistent hypertension 
with SBP from 140 to 159 mmHg and/or DBP from 90 to 99 mmHg, despite optimized 
anti-hypertensive treatment of ≥ 14 days and assured compliance, the following actions 
should be taken: 
• Reduce lucitanib to next lower dose level (see Table 8.A-3), or if at 2 mg QD 
lucitanib, withhold lucitanib treatment.  
• Ensure adequate control of BP below 140/90 mmHg including increasing the dose of 
the current antihypertensive agent(s) (if appropriate) and/or initiation of additional 
antihypertensive agents, as appropriate.  


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- 
Allow up to 14 days for BP to be controlled to baseline or Grade < 2.  
- 
If BP does not reduce to < 140/ 90 mmHg after 14 days, lucitanib should be 
reduced again, unless if at 2 mg QD lucitanib, whereby withhold lucitanib 
treatment. 
◦ 
Allow an additional 14 days for BP to be controlled to baseline or 
Grade < 2. 
◦ 
If BP decreases to < 140/90 mmHg within 14 days, resume lucitanib at the 
reduced dose. 
◦ 
If BP does not reduce to < 140/ 90 mmHg within the additional 14 days, 
lucitanib should be withheld for up to 14 days.  
◦ 
If BP remains at ≥ 140/90 mmHg after withholding lucitanib for 14 days, 
approval by the study’s medical monitor is required prior to re initiating 
lucitanib treatment. 
 
Confirmed Grade 3 Hypertension with No Hypertension-related Symptoms and No 
More than 1 Risk Factor 
If after starting the rucaparib and lucitanib combination, a patient has confirmed hypertension 
with SBP ≥ 160 mmHg and/or DBP ≥ 100 mmHg, with no hypertension-related symptoms 
and no more than 1 risk factor (defined as comorbidities that may increase hypertension-
related complications, eg, diabetes and/ or coronary artery disease), the following actions 
should be taken: 
• Continue lucitanib therapy.  
• Immediately start anti-hypertensive treatment or optimize current anti-hypertensive 
treatment. 
- 
Allow up to 48 hours for BP to be controlled (BP < 140/ 90 mmHg), with close 
follow-up by the treating physician.   
- 
If BP does not reduce to < 140/90 mmHg within 48 hours, lucitanib should be 
reduced to next lower dose level, or if at 2 mg QD lucitanib, withhold lucitanib 
treatment. 
- 
If BP does not reduce to < 140/90 mmHg within 48 hours despite lucitanib dose 
reduction and optimal anti-hypertensive therapy, withhold lucitanib.  
◦ 
If BP decreases to < 140/90 mmHg within 14 days, resume lucitanib at 
next lower dose level, or if withheld while receiving 2 mg QD lucitanib, 
resume at 2 mg QD. 
◦ 
If BP is not controlled < 140/90 mmHg) within 14 days after interruption of 
lucitanib and despite optimal anti-hypertensive treatment, lucitanib should 
be permanently discontinued. 
 
Confirmed Grade 3 Hypertension with Mildly Symptomatic Hypertension, Several Risk 
Factors, or Receiving 2 Anti-hypertensive Agents 


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If after starting the rucaparib and lucitanib combination, a patient has confirmed hypertension 
with SBP ≥ 160 mmHg and/or DBP ≥ 100 mmHg, in addition to any one of the following: 
1. mildly-symptomatic hypertension, defined as symptoms of headache, facial flushing, 
etc. in the absence of additional cardiac, neurological findings or major renal 
complications; or 
2. several risk factors (defined as comorbidities that may increase hypertension-related 
complications, eg, diabetes and/ or coronary artery disease)  
 
then the following actions should be taken: 
• Withhold lucitanib treatment. Immediate use of 2 or 3 anti-hypertensive agents 
may be considered in patients with no history of hypertension. For patients already on 
2 anti-hypertensive agents, with assured compliance, modification of the current 
anti-hypertensive therapy and/or adding a third agent should be considered. 
- 
The patient should be followed by the investigator closely to evaluate the 
response to anti-hypertensive treatment. 
- 
Allow up to 14 days for BP to be controlled (BP < 140/90 mmHg).  
- 
If BP decreases to < 140/90 mmHg within 14 days, resume lucitanib at next 
lower dose level (Table 8.A-3), or if withheld while receiving 2 mg QD 
lucitanib, resume at 2 mg QD.  
- 
If BP does not reduce to < 140/90 mmHg within 14 days, lucitanib should be 
permanently discontinued. 
 
Confirmed Hypertensive Crisis with Life-threatening Consequences 
If after starting the rucaparib and lucitanib combination, a patient has confirmed hypertensive 
crisis, defined as an increase in BP of ≥ 180 mmHg SBP and/ or ≥ 120 mmHg DBP) that can 
lead to life-threatening consequences (eg, cerebral stroke), then lucitanib treatment must be 
permanently discontinued. 
8.A.6.5.2 
Management of Treatment-emergent Proteinuria 
Patients will be regularly monitored for proteinuria by dipstick. Patients with early signs of 
proteinuria by dipstick (2+) should be closely monitored and proteinuria evaluated 
quantitatively (24 hrs protein excretion or protein-to-creatinine ratio).  
Proteinuria will be graded NCI CTCAE v5.0, as presented in Table 8.A-5. 
Table 8.A-5  NCI CTCAE Grading Scale for Proteinuria 
Grade 1 
1+ proteinuria; urinary protein < 1.0 g/24 hours 
Grade 2 
2+ proteinuria; urinary protein ≥ 1.0 to 3.4 g/24 hours 


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Guidelines for management of lucitanib-related proteinuria are listed in Table 8.A-6. 
Table 8.A-6  Management of Lucitanib-related Proteinuria 
Adverse Event 
Severity 
(CTCAE Grade) 
Dose Modification Action 
Proteinuria, first onset 
≥ 2 
Withhold lucitanib; monitored proteinuria by 
dipstick weekly at the investigational site.  
Upon recovery of proteinuria to Grade ≤ 1, 
resume lucitanib at the same dose; continue to 
monitor via dipstick. 
Proteinuria, second onset 
≥ 2 
Withhold lucitanib; perform quantitative 
assessment of 24-hr urinary protein.  
Upon recovery of proteinuria to Grade ≤ 1, 
resume lucitanib at the next lower dose; or if at 
2 mg QD, resume at 2 mg QD. 
Proteinuria, third onset 
≥ 2 
Repeat assessments and dose modifications as 
outlined above. 
Proteinuria, fourth onset 
≥ 2 
If proteinuria ≥ Grade 2 recurs following dose 
reductions to 2 mg QD, or if there is no recovery 
within 30 days at 2 mg QD, discontinue lucitanib 
treatment permanently. 
Abbreviations: NCI CTCAE = National Cancer Institute Common Terminology Criteria for Adverse Events; 
QD = once a day. 
 
8.A.6.5.3 
Management of Subclinical Hypothyroidism 
Plasma TSH and thyroid hormones levels should be measured, as part of clinical chemistry 
testing per the Schedule of Assessments (Table 8.A-7). Treatment with levothyroxine 
50 µg/day is recommended for patients with TSH values above 5 mIU/L, even if 
triiodothyronine (T3) and thyroxine (T4) are normal. Study drug dose modifications are not 
necessary. 
8.A.6.5.4 
Management of Decrease in Left Ventricular Ejection Fraction 
In case of observed decrease in LVEF or symptoms of heart failure, the following guidelines 
should be followed: 
• Perform ECHO or MUGA, as appropriate. 
Grade 3 
Urinary protein ≥ 3.5 g/24 hours 
Source:  NCI CTCAE, v5.0. 
Abbreviations: NCI CTCAE = National Cancer Institute Common Terminology Criteria for Adverse Events.  


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• If no signs of heart failure and LVEF ≥ 45% OR absolute drop from baseline 
≤ 15 ejection fraction percentage points, then continue lucitanib at the same dose level, 
and repeat the LVEF assessment. 
• Patient is symptomatic OR LVEF < 45% OR absolute drop from baseline > 15 ejection 
fraction percentage points, then hold lucitanib until resolution (LVEF ≥ 50% and 
asymptomatic). If resolution occurs within 3 weeks, lucitanib can be resumed at a 
reduced dose (Table 8.A-3), otherwise discontinue lucitanib permanently. 
• No recovery OR LVEF < 20%, then discontinue lucitanib permanently and maintain 
follow-up as per Section 10.8. 
 
8.A.6.5.5 
Management of Posterior Reversible Encephalopathy Syndrome 
If a patient presents with symptoms suggestive of PRES, eg, persisting headache not 
responsive to usual analgesics, confusion, visual symptoms, seizures and coma, immediately 
withhold lucitanib and consider performing all relevant clinical and radiological 
examinations (eg, neurological consultation, MRI) to ensure early diagnosis and treatment of 
this syndrome. A follow-up MRI should be performed to confirm the diagnosis of PRES, and 
if confirmed, lucitanib must be permanently discontinued. 
8.A.6.6 
Treatment Arm A Study Drug Compliance and Accountability 
Rucaparib treatment compliance is described in Section 5.7, and lucitanib compliance will be 
recorded analogously. Study drug accountability is described in Section 5.8. 
 Prior and Concomitant Therapy 
Refer to Section 6 for prior and concomitant therapy restrictions and information that is 
general across all treatment arms of this study. Additional information specific to the 
rucaparib and lucitanib combination arm are described in this section. 
Due to the known risk of hypertension with lucitanib treatment, sites should counsel patients 
on limiting salt intake to less than 4 g/day. 
8.A.7.1 
Other Concomitant Medications 
Drugs with a known risk for prolonged QT interval and Torsades de Pointes should be 
avoided. 
For the rucaparib and lucitanib combination arm, strong inhibitors of CYP2C8 or CYP3A4 
are contraindicated during the study. Should acute treatment with a strong inhibitor of 
CYP2C8 be deemed necessary, lucitanib must be temporarily withheld. Lucitanib may be 
resumed after a minimum of 7 days of ending the acute treatment with a strong inhibitor of 
CYP2C8. Concomitant administration of strong inducers of CYP3A4 are not permitted at 
any time during treatment. Moderate CYP2C8 and CYP3A4 inhibitors are not recommended. 
Strong inducers of CYP3A4 may reduce the plasma concentrations of lucitanib and should be 
avoided. Refer to Appendix 2. 


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 Study Procedures and Methods for Treatment Arm A 
8.A.8.1 
Schedule of Assessments:  Treatment Arm A 
Table 8.A-7 summarizes the procedures and assessments to be performed for all patients in 
Treatment Arm A (Phase 1 and Phase 2).  
Table 8.A-8 summarizes the timing of collection of PK samples for all patients in Treatment 
Arm A.  
The investigator or their designee shall discuss with each patient the nature of the study and 
its requirements. To participate in the study, written informed consent must be obtained from 
each potential patient prior to any study activities (see Section 11.2). The information on the 
IRB/IEC-approved consent form should be translated and communicated in the language the 
patient (or legally authorized representative) can understand.  
The screening period begins with the first study-specific procedure, performed outside 
standard of care, and only after written consent for study participation has been provided. 
Additionally, patients participating in the optional tumor tissue biopsy at the time of 
radiologic disease progression/treatment discontinuation must provide additional written 
consent for this procedure. 
All procedures and assessments are to be completed within ± 3 days of the scheduled time 
unless otherwise stated.  


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Table 8.A-7 Schedule of Assessments for All Patients in Treatment Arm A (Phase 1b and Phase 2) 
 
Screening Phase 
Treatment Phase 
(28-day cycles ± 3 days) 
Post Treatment Phase 
 
Cycles 1 and 2 
Cycles 3+ 
Study Day 
Day -56 
to Day -1 
Day -28 
to Day -1 
Day -14 
to Day -1 
Day 
1 
Day 
4a 
Day 
15 
Day 1 
End of 
Treatment 
28-day  
Safety FUb 
Procedurec 
 
Informed Consent 
X 
 
 
 
 
 
 
 
 
Medical/Oncology History (Section 7.1) 
X 
 
 
 
 
 
 
 
 
Tumor Tissue Sample (Section 7.5.1)d 
X 
 
 
 
 
 
 
 
 
Physical Examination (Section 7.4.5) 
 
X 
 
X 
 
 
X 
X 
X 
Vital Signs (Section 7.4.3) 
 
X 
 
X 
X 
X 
X 
X 
X 
12-lead ECG (Section 7.4.4) 
 
X 
 
X 
 
 
X 
X 
 
LVEF Assessment (Section 8.A.8.2.1) 
 
X 
 
 
 
 
 
 
 
Prior/Concomitant 
Medications/Procedures (Section 7.2)e 
 
X 
 
X 
X 
X 
X 
X 
X 
Disease Assessment/Tumor Scansf 
(Section 7.3.1) 
 
X 
 
 
 
 
X 
X 
 
ECOG Performance Status 
 
X 
 
X 
 
 
X 
X 
X 
Hematology (Section 7.4.2) 
 
 
X 
X 
 
X 
X 
X 
X 
Chemistry, including TSH and T3/T4 
(Section 7.4.2 and Section 8.A.8.2.2) 
 
 
X 
X 
 
X 
X 
X 
X 
Urinalysis (Section 7.4.2) 
 
 
X 
X 
 
X 
X 
X 
 
Serum or plasma Pregnancy Test 
(WOCBP only) (Section 7.4.2) 
 
 
X 
X 
 
 
X 
X 
 
CA-125 Measurement for HGOC 
patients (Section 7.5.2)g 
 
 
X 
X 
 
 
X 
X 
 
Pharmacogenomics Blood Sample 
(Section 7.5.3)h 
 
 
 
X 
 
 
 
 
 


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Table 8.A-7 Schedule of Assessments for All Patients in Treatment Arm A (Phase 1b and Phase 2) 
 
Screening Phase 
Treatment Phase 
(28-day cycles ± 3 days) 
Post Treatment Phase 
 
Cycles 1 and 2 
Cycles 3+ 
Study Day 
Day -56 
to Day -1 
Day -28 
to Day -1 
Day -14 
to Day -1 
Day 
1 
Day 
4a 
Day 
15 
Day 1 
End of 
Treatment 
28-day  
Safety FUb 
Procedurec 
 
Blood Sample for ctDNA Analysis 
(Section 7.5.2)i  
 
X 
 
X 
 
 
X 
X 
X 
Blood Sample for AAG Analysis 
(Section 8.A.8.2.2) 
 
 
 
X 
 
 
 
 
 
Rucaparib and Lucitanib Administrationj 
 
 
 
X 
X 
X 
X 
 
 
Adverse Eventsk (Sections 10.7 and 
10.8) 
(X) 
(X) 
(X) 
X 
X 
X 
X 
X 
X 
Post-progression Tumor Tissue Biopsy 
(Section 7.5.1)l 
 
 
 
 
 
 
 
X 
 
Blood Samples for PK  
Refer to Table 8.A-8 for sampling schedule 
 
Abbreviations: AAG = α1 acid glycoprotein; AML = acute myeloid leukemia; CA-125 = cancer antigen 125; ctDNA = circulating tumor deoxyribonucleic acid; 
ECG = electrocardiogram; ECOG = Eastern Cooperative Oncology Group; FU = Follow-up; OC = ovarian cancer; INR = international normalized ratio; 
LVEF = left ventricular ejection fraction; MDS = myelodysplastic syndrome; PK = pharmacokinetics; T3 = free triiodothyronine; T4 = free thyroxine; 
TSH = thyroid stimulating hormone; WOCBP = women of child-bearing potential. 
a 
Patients are required to have a study visit on Day 4 of Cycle 1 only. There is no ± 3 day window for this visit. 
b 
Follow-up Visit should occur 28 days (±7) from the last dose of study drug or can be performed on the date of discontinuation if that date is at least 28 days 
from last dose, whichever is later. Chemistry and hematology are only necessary at FU Visit, if toxicities are present. The follow up visit should be 
conducted in person. 
c 
The study visit window in the treatment phase is ± 3 days, unless noted otherwise for a particular assessment. Study visits should take into account the 
patient’s investigational product supply. Only 1 cycle of oral study drug will be dispensed to the patient on Day 1 of each cycle. 
d 
The tumor tissue sample must be adequate for genomic testing. If archival tissue sample is inadequate or unavailable, a more recently obtained tissue sample 
will be required prior to administration of study drug. Refer to the Laboratory Manual for details on tissue adequacy, sample collection and handling 
instructions. 


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e 
Patients taking warfarin should have INR monitored regularly per standard clinical practice (Section 6.5). Patients taking digoxin should have their digoxin 
levels monitored after starting rucaparib and then regularly per standard clinical practice (Section 6.6).  
f 
Disease assessments to consist of clinical examination and appropriate imaging techniques per RECIST will occur every 8 calendar weeks (up to ±1 week 
prior is permitted) for the first 18 months following initiation of combination study treatment, then every 16 weeks until radiological disease progression as 
assessed by the investigator, death, loss to follow-up, withdrawal from study, or study termination. Other complementary studies may be performed if 
clinically indicated. The same methods used to detect lesions at baseline are to be used to follow the same lesions throughout the clinical study. End-of-
Treatment scans not required if disease progression determined and patient is not continuing study treatment. 
g 
CA-125 measurement should be performed for patients with ovarian cancer at screening and on Day 1 of every subsequent cycle, at treatment 
discontinuation, as clinically indicated. If a patient discontinues treatment for reasons other than disease progression, then a sample should be taken at the 
same time as radiological imaging and ctDNA sampling. 
h 
If sample is not collected on Day 1 of Cycle 1, it should be collected as soon as possible thereafter. 
i 
Day 1 (before dosing) of Cycle 1 through Cycle 6 and at the same time as radiological imaging and CA-125 sampling (where feasible), at the End of 
Treatment, and at the 28-day Follow-up Visit. If a patient discontinues treatment for reasons other than disease progression, then a sample should be taken at 
the same time as radiological imaging and CA-125 (for ovarian cancer patients). 
j 
First dose of both study drugs in Cycle 1 should be administered within 3 days after a patient having been confirmed as meeting the enrollment criteria. 
Administration is continuous (not just the days specified in the table). Refer to Section 5.5 (rucaparib) and Section 8.A.6.3 (lucitanib) for administration 
guidelines. Study treatment continues in 28-day cycles until disease progression, unacceptable toxicity, patient or physician request to discontinue, death, 
initiation of any other cancer therapy, positive pregnancy test, or termination of the study. 
k 
AEs, SAEs, and AESIs that occur after first administration of study drug through to 28 days after last dose of study drug(s). In addition, SAEs that were 
related to a screening procedure will also be recorded. Ongoing SAEs, AESIs, or treatment-related Grade 3/4 AEs will be followed to resolution or 
stabilization. After the Safety Follow-up, only SAEs considered as potentially study-drug related (including serious reports of pneumonitis and similar 
events, ie, interstitial lung disease, pulmonary fibrosis, acute interstitial pneumonitis, alveolitis necrotizing, alveolitis, hypersensitivity pneumonitis, and 
organizing pneumonia, if considered to be related to study drug),  and AESIs of MDS and AML, regardless of causality, will be recorded in the eCRF. 
l 
An optional tumor biopsy may be collected at or following disease progression until the start of the next treatment. Additional consent is required. Refer to 
the Laboratory Manual for details on sample collection and handling instructions. 
 
 


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Table 8.A-8 Pharmacokinetic Sample Collections in Treatment Arm A (Phase 1b and Phase 2) 
Study Visit 
Lucitanib PK 
Rucaparib PK 
Cycle 1 
(Phase 1ba) 
D15b 
Predosec 
Predosec 
Post-morning dose:  
0.5, 1, 1.5, 2.5, 4, 6 and 8 hrs 
Post-morning dose:  
0.5, 1, 1.5, 2.5, 4, 6 and 8 hrs 
D16d 
Predosec 
_ 
Cycle 2-4 
(Phase 1ba and Phase 2) 
D1 
Predosec 
Predosec 
Abbreviations: D = Day; hrs = hours; PK = pharmacokinetics. 
a 
Phase 1b includes patients in the dose-escalation phase and the RP2D expansion. 
b 
On Cycle 1 Day 15, doses of rucaparib and lucitanib must be taken at the same time on an empty stomach, ie, at least 2 hours prior and 1 hour after any 
meal. For Phase 1b for Cycle 1 Day 15, a time window of ±5 minutes for specimen collections up to 2 hours and ±15 minutes from 2.5 to 8 hours. 
c 
Predose refers to collection prior to the morning dose of both rucaparib and lucitanib. The predose specimen collection may be performed 30 minutes 
before taking the next dose of study drug. 
d 
Patients do not need to stay overnight for Cycle 1 Day 16. A time window of ±1 hour for specimen collection (of lucitanib) is permitted 24 hours after the 
Cycle 1 Day 15 dose of lucitanib and within 30 minutes before taking the next dose. 
Notes: Collection of the actual time(s) of dose administration is essential for both rucaparib and lucitanib. 
Refer to the (Treatment Arm A) Laboratory Manual for details on sample handling and processing. 
 
 


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8.A.8.2 
Methods of Data Collection: Arm A 
See Section 7 for methods of data collection that are general across all treatment arms of this 
study. Additional information specific to the rucaparib and lucitanib combination arm are 
described in this section. 
8.A.8.2.1 
Left Ventricular Ejection Fraction Assessment 
LVEF will be assessed by ECHO or MUGA during screening. Patients must meet the LVEF 
criteria (Inclusion Criteria #6). If it is clinically indicated, LVEF assessments can be 
performed at other times during the study. 
8.A.8.2.2 
Additional Clinical Laboratory Investigations 
In addition to the laboratory assessments described in Section 7.4.2, the following will be 
tested at the same timepoints as chemistry testing: TSH, free triiodothyronine (T3; fT3), free 
thyroxine (T4, fT4), TSH with reflexive fT3 and fT4 if TSH is abnormal on treatment. 
A blood sample for α1-acid glycoprotein (AAG) analysis will be taken predose on Day 1 of 
Cycle 1 for all patients. 
8.A.8.2.3 
Pharmacokinetic Sample Collection 
For all patients in Phase 1b and Phase 2, plasma samples are to be collected for trough level 
PK analysis of oral study drug within 30 minutes before the morning dose of rucaparib and 
daily dose of lucitanib on Day 1 of Cycles 2, 3, and 4. Plasma samples are to be collected 
approximately 12 hours after the last oral dose of rucaparib and approximately 24 hours after 
the last dose of lucitanib, but prior to the next oral dose (ie, typically within 30 minutes prior 
to dosing). If study drug dosing is temporarily withheld on a day where PK specimens were 
to be collected, plasma samples for rucaparib and lucitanib PK should still be collected at the 
nominal collection days and times prior to the originally planned dosing. 
On Day 15 of Cycle 1, an intensive PK sampling collection will commence after the morning 
dose of rucaparib and daily dose of lucitanib on an empty stomach (see Section 8.A.6.3). On 
this day, these 2 doses should be taken together to facilitate PK sampling. Plasma samples 
will be taken as indicated in Table 8.A-8. For Phase 1b for Cycle 1 Day 15, a time window of 
± 5 minutes for specimen collections up to 2 hours and ± 15 minutes from 2.5 to 8 hours. 
Patients do not need to stay overnight for Cycle 1 Day 16. A time window of ± 1 hour for 
specimen collection at the 24-hour timepoint is permitted. 
A central laboratory will be used for bioanalysis of plasma rucaparib and lucitanib 
concentration measurement. Please refer to the Laboratory Manual for details on collection 
and processing of blood PK samples. 


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 Planned Statistical Methods: Treatment Arm A 
The statistical methods that are general across treatment arms are described within 
Section 9.  
The determination of sample sizes for Treatment Arm A, Phase 1b and Phase 2 cohorts are 
described below. 
8.A.9.1 
Determination of Sample Size 
The total enrollment planned for evaluation of rucaparib in combination with lucitanib is up 
to 135 patients. 
Phase 1b is based on a standard 3+3 dose-escalation design, and the overall sample size 
depends on the occurrence of safety findings, specifically, DLTs, observed at the different 
dose regimens. A minimum of 6 and maximum of approximately 55 patients across all dose 
cohorts may be enrolled. Additional patients may be enrolled to evaluate other dose levels or 
schedules as described in Section 8.A.4.2.1. Additional patients may be enrolled into a 
particular dose cohort if a patient already enrolled into that same dose cohort does not meet 
the criteria for the DLT-evaluable population, defined in Section 9.2. 
A Simon 2-stage design will be used to evaluate efficacy (confirmed overall response of CR 
or PR) of rucaparib in combination with lucitanib in each of the Phase 2 cohorts. The sample 
sizes for each Phase 2 cohort was determined based on a null hypothesis (H0), which 
specifies a response proportion that if not reached (response is less than that specified), 
further investigation would not be warranted, and an alternative hypothesis (H1), which 
specifies a response proportion that if observed would warrant further investigation of the 
rucaparib and lucitanib combination treatment in the corresponding cohort. 
Phase 2 Cohort A1: Patients with Platinum-sensitive, gBRCAwt HGOC 
Up to 49 patients (31 patients enrolled in Stage 1 and 18 patients enrolled in Stage 2) will be 
used to evaluate efficacy. After the first 31 patients either a) complete 16 weeks of study 
treatment or b) discontinue study treatment prior to completing 16 weeks, an interim 
(Stage 1) analysis will be performed. If ≤ 10 of these 31 patients have a confirmed overall 
response (CR or PR per investigator assessment), the sponsor and key participating 
investigators will evaluate overall benefit:risk for patients and determine whether or not to 
continue further enrollment. If 11 or more patients in Stage 1 have a confirmed overall 
response, then enrollment of the additional 18 patients in Stage 2 will be completed. 
Characteristics of this design include:  
• H0: p ≤ 0.35; 
• H1: p ≥ 0.50; and 
• 80% power at significance level = 0.10 (one-sided). 
 


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If Stage 2 is fully enrolled and ≥ 22 out of 49 total patients have a confirmed overall 
response, then per the design, the null hypothesis is rejected, and the rucaparib and lucitanib 
combination warrants consideration of further investigation in patients with platinum-
sensitive, BRCAwt ovarian cancer. 
Phase 2 Cohort A2: Patients with Platinum-resistant, gBRCAwt HGOC 
Up to 31 patients (16 patients enrolled in Stage 1 and 15 patients enrolled in Stage 2) will be 
used to evaluate efficacy. After the first 16 patients either a) complete 16 weeks of study 
treatment or b) discontinue study treatment prior to completing 16 weeks, an interim 
(Stage 1) analysis will be performed. If ≤ 1 of these 16 patients have a confirmed overall 
response (CR or PR per investigator assessment), the sponsor and key participating 
investigators will evaluate overall benefit:risk for patients and determine whether or not to 
continue further enrollment. If 2 or more patients in Stage 1 have a confirmed overall 
response, then enrollment of the additional 15 patients in Stage 2 will be completed.  
Characteristics of this design include:  
• H0: p ≤ 0.10; 
• H1: p ≥ 0.25; and 
• 80% power at significance level = 0.10 (one-sided). 
 
If Stage 2 is fully enrolled and ≥ 6 out of 31 total patients have a confirmed overall response, 
then per the design, the null hypothesis is rejected, and the rucaparib and lucitanib 
combination warrants consideration of further investigation in patients with platinum-
resistant, BRCAwt ovarian cancer. 
 
 


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8.B TREATMENT ARM B: RUCAPARIB AND SACITUZUMAB 
GOVITECAN 
 Antibody-drug Conjugates 
Antibody-drug conjugates (ADC) are a class of potent bioconjugated drugs designed to target 
specific cells in patients with cancer. They are produced by linking the unique targeting 
capabilities of a monoclonal antibody with a cytotoxic chemotherapy agent. Such targeting 
methods often provide a selective advantage for localizing these agents to tumors, with 
improved therapeutic responses as compared to the agent alone, but careful development and 
evaluation are required. Paramount is that the conjugate preserves the activity of the 
cytotoxic agent without compromising the antibody's ability to bind to its target. Secondly, 
the therapeutic agent should be active at relatively low concentrations, preferably nanomolar 
levels. This requirement reflects the fact that for antibody conjugates to be active, they need 
not only to deliver the therapeutic agent selectively to the tumor, but the conjugate must be 
internalized into the tumor cell, with the agent being released in an active form.  
ADCs are gaining interest as a targeted therapy, since they should discriminate between the 
normal tissue and tumor tissue, which generally expresses higher levels of the antibody 
target. Brentuximab vedotin (Adcetris®), an anti-CD30 monoclonal antibody attached to the 
cytotoxic agent, monomethyl auristatin E (MMAE), is approved in both the US and EU for 
the treatment of relapsed Hodgkin lymphoma (HL) and systemic anaplastic large cell 
lymphoma (sALCL).59,60 A second ADC, trastuzumab emtansine (T-DM1; Kadcyla®), which 
consists of the recombinant anti-human epidermal growth factor receptor 2 (HER2) 
monoclonal antibody trastuzumab (Herceptin®) conjugated to the cytotoxic agent, emtansine 
(DM1), is approved in the US for the treatment of patients with HER2-positive metastatic 
breast cancer who have received prior treatment with trastuzumab and a taxane 
chemotherapy.61 
 Sacituzumab Govitecan Background 
Sacituzumab govitecan (IMMU-132) is a novel ADC that is composed of the following 
3 components: 
1. The humanized monoclonal antibody, hRS7 IgG1к, which binds to Trop-2 (trophoblast 
cell-surface antigen, also known as EGP-1, epithelial glycoprotein-1). 
Trop-2 is a cell surface, transmembrane calcium signal transducer glycoprotein belonging 
to the TACSTD gene family, which is highly expressed in many epithelial cancers, 
particularly metastatic sites,62 with much lower expression in normal tissues.63 Trop-2 has 
been implicated in oncogenesis, often being found in more aggressive tumors.64 The 
antibody was initially developed as a murine monoclonal antibody by the immunization 
of mice with a fresh specimen of a human lung cancer. The properties of the parent 
murine antibody have been extensively described.65-70 


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2. The camptothecin-derived agent, SN-38, a topoisomerase 1 inhibitor. 
SN-38 is the active metabolite of irinotecan (camptothecin-11; Camptosar®), which is 
approved as treatment for metastatic colorectal cancer.71 Only 5% of irinotecan is 
converted to the active SN-38 form by esterase activity residing primarily in the liver, 
though there are also esterases in the tumor that can cleave irinotecan to SN-38.72 SN-38 
is not soluble in aqueous media, and hence the reason a water-soluble irinotecan 
derivative was prepared. 
3. A linker, with the company designation CL2A, which binds SN-38 to the antibody. 
 
8.B.2.1 
Mechanism of Action of Sacituzumab Govitecan 
Sacituzumab govitecan (IMMU-132) is an ADC composed of hRS7, a humanized IgG1κ 
monoclonal antibody, SN-38, a camptothecin analog, and CL2A, a linker which couples 
SN-38 to hRS7.  
Trop-2 is a cell surface antigen overexpressed in many epithelial cancers and has been linked 
to aggressive disease and poor prognosis. The antibody component binds to Trop-2 such that 
the ADC concentrates on tumor cell surfaces. SN-38 is the active metabolite of irinotecan 
and a topoisomerase I inhibitor that induces single-stranded DNA breaks during replication. 
If unrepaired, these breaks progress to double-stranded DNA breaks and results in cell death. 
The CLA2 linker is unique in that it is subject to pH-dependent hydrolysis. Following 
internalization of the ADC-antigen complex, SN-38 is released in the acidic lysosome and 
kills the target cells.73,74 In addition, SN-38 can be cleaved from extracellular, surface-bound 
ADC due to the acidic pH of the tumor microenvironment. The released drug diffuses into 
neighboring cells in an antigen-independent manner, and this leads to death of cells in the 
immediate proximity of the target-expressing cells. These 2 mechanisms of action combine 
to enable sacituzumab govitecan to target and kill cancer cells that over-express Trop-2, as 
well as, other cells in the tumor with low or no Trop-2 expression.  
8.B.2.2 
Nonclinical Experience 
8.B.2.2.1 
Pharmacology 
In vitro cytotoxicity of sacituzumab govitecan was assessed in 6 different cell lines 
representative of several different epithelial tumors; PC-3 (prostate), Calu-3, COLO 205, 
Capan-1, SK-MES-1 and BxPC-3.  In general, the IC50 values ranged from 1.95 nM to 
23.14 nM.75  
In vivo preclinical testing of sacituzumab govitecan was performed in nude mouse-human 
cancer xenograft models using a variety of different human cancer cell lines, eg, NSCLC, 
colorectal, pancreatic, gastric, squamous cell lung, and triple-negative breast cancer (TNBC) 
cancers.75-77 Pronounced antitumor activity and significant inhibition of tumor growth was 
shown in all xenograft models, with the exception of a single squamous cell lung cancer 
xenografts, where sacituzumab govitecan was superior to saline or unconjugated hRS7, but 
not superior to a nonspecific antibody or irinotecan at the MTD. 


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8.B.2.2.2 
Pharmacokinetics 
Toxicokinetic analysis of the 3-month repeat-dose study in Cynomolgus monkeys showed a 
dose-related exposure with no relevant gender differences. SN-38G readily appeared in 
serum with mean tmax ranging from 4.0 to 12 hours after the first dose. On average the Free 
SN-38 exposure was 2.26% and 1.52% of the Total SN-38 exposure, respectively, based on 
the AUC0-168 and Cmax values. 
8.B.2.2.3 
Toxicology 
In acute toxicity studies in Swiss-Webster Mice, sacituzumab govitecan at doses of up to 
750 mg/kg/dose (ie, cumulative doses of up to 1500 mg/kg) caused minimal loss (< 10%) in 
body weight. There was no evidence of hematological toxicity, and no abnormal histology 
findings. Transient increases in hepatic transaminases were observed that returned to normal 
by the end of the study. 
In Cynomolgus monkeys, sacituzumab govitecan administered 50 mg/kg/dose (human 
equivalent dose [HED] = 16 mg/kg/dose) for 4 treatment cycles (Days 1 and 8 of a 21-day 
cycle) was considered a No-Observed-Adverse-Effect-Level (NOAEL) and 120 mg/kg/dose 
administered 3 days apart was associated with lethality. In monkeys, target organs included 
the female reproductive tract, skin (hair loss, pigmentation), kidney (periarteritis), lymphoid 
organs (lymphoid depletion), bone marrow (reduced cellularity) with concomitant reductions 
in red cells, white cells and platelets and the gastrointestinal tract (necrosis, erosions, 
inflammation, fibrosis, hemorrhage, edema). 
Local tolerance was evaluated in the Good Laboratory Practice (GLP)-compliant monkey 
studies. Although changes were observed at the injection site, the study pathologist 
interpreted these findings as related to procedural trauma and not the test article. These 
changes consisted of mild to moderate perivascular hemorrhage, moderate hemorrhage in the 
dermis and subcutis, and minimal to mild perivascular mixed cell infiltration. 
SN-38 was negative for mutagenicity in a bacterial reverse mutation test and was found to be 
clastogenic in an in vitro mammalian cell micronucleus test. Neither the carcinogenicity, nor 
effects of sacituzumab govitecan on fertility, early embryonic development or pre- and 
post-natal development have been assessed. However, SN 38 is a camptothecin and hence 
might be carcinogenic. Furthermore, SN-38 is a known developmental toxicant.71 
8.B.2.3 
Clinical Experience 
To date, the clinical experience with sacituzumab govitecan is derived from 3 ongoing 
clinical studies. IMMU-132-01 is a Phase 1/2 multi-center US study that was originally 
designed to obtain initial safety and dose-finding data of sacituzumab govitecan monotherapy 
in patients with advanced relapsed/refractory metastatic epithelial cancers, including ovarian, 
TNBC, prostate (hormone refractory), lung (non-small cell and small-cell), head and neck 
(squamous cell), esophageal, gastric, colorectal, pancreatic, hepatocellular, renal (clear cell) 
and urinary bladder cancers. This study was expanded with a Phase 2 portion that only 
enrolled patients with TNBC, lung (non-small cell and small-cell), or urothelial cancer (UC). 
Both phases of the study are closed to enrollment. The Phase 1 portion of the study has been 


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completed, while there are still patients under follow-up in the Phase 2 portion. Based on 
encouraging data noted in the TNBC cohort of IMMU-132-01, a Phase 3 randomized, 
controlled study was initiated, IMMU-132-05. In addition, based on activity noted in the UC 
cohort of IMMU-132-01, a Phase 2 study (IMMU-132-06) in metastatic UC was recently 
initiated (not yet described in the sacituzumab govitecan IB). Recruitment in both IMMU-
132-05 and IMMU-132-06 studies is ongoing. 
Twenty-five patients were included in the Phase 1 portion of IMMU-132-01, with 
sacituzumab govitecan doses as high as 18 mg/kg given on Day 1 and 8 of a 21-day 
treatment cycle.78 Neutropenia was the dose-limiting toxicity at this level, with the MTD 
declared to be 12 mg/kg. Most of the other AEs at all dose levels were Grade 2 or lower. 
Fatigue, alopecia and occasional mild to moderate diarrhea were some of the more common 
non-hematological toxicities, with 2 patients reporting a rash. While 12 mg/kg was 
considered the MTD, there was tendency for patients treated at this level to have delays in 
their dose schedule, as well as dose reductions. Ultimately, 10 mg/kg (days 1 and 8 of a 
21-day cycle) was selected for further development. 
As of November 2018 (after the release of the current sacituzumab govitecan IB v6, dated 
28 Sept 2018), a total of 650 patients have been treated with sacituzumab govitecan in the 
3 clinical studies with the majority treated at the 10-mg/kg dose level.  
8.B.2.3.1 
Efficacy 
Efficacy in the relevant populations, using recently-published data, are shown below. 
Triple-negative Breast Cancer 
As of 30 Jun 2017, 110 patients with TNBC were enrolled in Study IMMU-132-01 who have 
had at least 2 prior therapies in the metastatic setting and were treated at the 10 mg/kg dose 
of sacituzumab govitecan had an assessable radiographic response measured by 
RECIST v1.1. Based on best response, there were 3 confirmed CRs and 33 confirmed PRs, 
resulting in a current ORR of 34% (37/110); the clinical benefit rate (CR + PR + stable 
disease [SD] > 6 months) was 45%.79 Kaplan-Meier graphs of PFS and overall survival (OS) 
generated for all treated patients show current estimated median values of 5.5 and 12.7 
months, respectively. 
Urothelial Cancer 
Based on data presented at the European Society for Medical Oncology (ESMO) conference 
in 2017, Tagawa, et al80 reported an ORR of 34% in 41 relapsed metastatic UC patients. 
Majority of patients had received platinum therapy with 14 of the 41 having received 
immunotherapy prior to entering the study. Patients had a median duration of response of 


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12.6 months, a median PFS of 7.1 months (95% CI, 5.0-10.7) and a median OS of 16.1 
months (95% CI, 10.5-17.7). 
8.B.2.3.2 
Safety 
Based on recently updated results, internal to the sponsor of sacituzumab govitecan, the 
safety profile of sacituzumab govitecan was characterized based on 420 patients with various 
epithelial cancers in the Overall Safety Population in Study IMMU-132-01. The most 
frequent AEs by MedDRA (Medical Dictionary for Regulatory Activities) system organ class 
(SOC) were gastrointestinal disorders (91%), followed by general disorders and 
administration site conditions (76%), and blood and lymphatic system disorders (66%). 
Infections occurred in 43% of patients. The most frequent AEs by preferred term of any NCI 
CTCAE grade were nausea (67%), diarrhea (62%), fatigue (53%), vomiting (44%), alopecia 
(42%), anemia (41%), and neutropenia (41%). Febrile neutropenia occurred in 6%. Serious 
adverse events were experienced by 40% of patients; the most frequent were febrile 
neutropenia (4%), diarrhea, pneumonia, and vomiting, (3% each), and dyspnea, nausea, and 
neutropenia (2% each). 
8.B.2.3.2.1 
Risks Associated with Antibody Administration 
When any antibody product is administered, the possibility of an allergic reaction, such as 
itching, erythema, hives, or anaphylaxis, which can manifest as bronchospasm or 
hypotension, needs to be considered. A physician should be available and supplies of 
epinephrine, antihistamine, and corticosteroid should be readily accessible when a patient 
receives sacituzumab govitecan infusion. In the event of an anaphylactic reaction, 
sacituzumab govitecan infusion should be stopped immediately and permanently 
discontinued. A patient who has such an allergic reaction should not receive additional 
sacituzumab govitecan. Other reversible and non-life-threatening potential side effects 
associated with antibody administration include constitutional symptoms such as chills, 
fever, myalgia, and malaise. These side effects can be treated symptomatically (refer to 
Section 8.B.6.5.1 for management of infusion-related reactions). 
8.B.2.3.3 
Pharmacokinetics and Immunogenicity 
Four analytes were measured to characterize the PK of the sacituzumab govitecan: 1) total 
antibody (hRS7 + hRS7-SN-38); 2) free SN-38 (the cytotoxic payload, not covalently bound 
to sacituzumab govitecan); 3) SN-38 glucuronide (SN-38G, an inactive metabolite of SN-38, 
not covalently bound to sacituzumab govitecan); and 4) total SN-38 (free SN-38 + hRS7-SN-
38). Furthermore, an analytical method for the detection of anti-IMMU-132 antibodies has 
been established to support the assessment of immunogenicity. 
The clinical pharmacology of SN-38 once released from sacituzumab govitecan is considered 
comparable to that of SN-38 released from irinotecan.  
Serial PK samples were available for 55 patients of the metastatic TNBC target population in 
Study IMMU-132-01, and peak/trough samples were available for 4 patients. Since all 
sampled patients were part of the target population, they had received a sacituzumab 
govitecan starting dose of 10 mg/kg; but some patients had PK samples taken after dose 


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reduction to 7.5 mg/kg. Concentration-time curves, shown for sacituzumab govitecan 
(IMMU-132), free SN-38, and total SN-38, appeared to be approximately parallel with a 
slight delay in Cmax for free SN-38.  
The metabolism of sacituzumab govitecan is mediated by both catabolism of the antibody 
and metabolism of the released payload, SN-38. Since the protein portion of sacituzumab 
govitecan is expected to be catabolized into individual amino acids in vivo, metabolism 
studies were not conducted for the antibody component. The metabolism of SN-38 is well 
described in the literature.71,72,81 Briefly, SN-38 is highly (~95%) bound to human plasma 
proteins, predominantly albumin.71 SN-38 can be conjugated to glucuronide in the liver by 
UGT1A1 forming the inactive metabolite SN-38G. Literature suggests that SN-38 may also 
be metabolized by CYP3A4; however, clinical implications of this finding have not yet been 
evaluated. UGT1A1 activity is reduced in people with genetic polymorphisms that lead to 
reduced enzyme activity, such as the UGT1A1*28 polymorphism. Metabolism of SN-38 is 
impaired in patients with such UGT1A1*28 polymorphisms.71   
Studies of the excretion of sacituzumab govitecan have not been conducted. SN-38 and 
SN-38G are reported to be primarily excreted through the hepatobiliary route, with lesser 
amounts detected in the urine.71,72,81 
 Rationale for Rucaparib and Sacituzumab Govitecan Combination 
Agents that inhibit topoisomerase 1, including irinotecan, have demonstrated synergy with 
PARP inhibitors in a variety of human tumor cell lines, including ovarian and breast 
cancers.5,6 The combination of a PARP inhibitor (including rucaparib) and sacituzumab 
govitecan demonstrated synergistic growth inhibition, increased double-stranded DNA 
breaks, and accumulation of cells in the S-phase of the cell cycle when assessed in human 
TNBC cell lines.82 These effects were observed regardless of BRCA1 or 2 mutation status. 
Taken together, these data support the rationale for the evaluation of the combination of 
rucaparib and sacituzumab govitecan clinically.  
It is notable that a study of the PARP inhibitor, veliparib, combined with the topoisomerase 1 
inhibitor, topotecan, showed a mechanistic interaction between the 2 drugs, resulting in 
delayed repair of Topo1-mediated DNA damage, despite there being some difficulties with 
synergistic hematologic toxicities.8 In addition, the PARP inhibitor, olaparib, has been shown 
to potentiate the cytotoxicity of SN-38, the active metabolite in irinotecan and topotecan, 
irrespective of MMR status in a variety of MMR-deficient or MMR-efficient cell lines.7 
8.B.3.1 
Dose and Duration Rationale  
Because synergistic effects as well as additive toxicities are possible, dose escalation for this 
combination will begin with starting doses lower than the established or recommended 
single-agent dose for either study drug. As safety and efficacy for oral rucaparib have been 
established using BID dosing, and the dosing schedule for sacituzumab govitecan (Day 1 and 
Day 8 in 21-day cycles) has been established in prior single-agent studies, these schedules 
will be followed in the current study. The starting doses will be oral rucaparib 300 mg BID 
with IV sacituzumab govitecan 6 mg/kg on Day 1 and Day 8 of each cycle. Modulation of 


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the doses of each study drug, rather than their schedules, is the intended approach to 
investigating the MTD and RP2D for the combination of rucaparib and sacituzumab 
govitecan. 
8.B.3.2 
Expansion Cohorts Rationale 
As previously described, favorable nonclinical data for this combination in both TNBC and 
ovarian cancer support the inclusion of patients with these underlying tumors. Clinical data 
for sacituzumab govitecan in advanced, metastatic UC have demonstrated significant and 
durable responses in patients with heavily pre-treated disease (Section 8.B.2.3.1). Genomic 
LOH is a biomarker of HRD that has been associated with PARP inhibitor sensitivity in 
ovarian cancer, and an analysis of The Cancer Genome Atlas (TCGA) demonstrated that 
many UC tumors have high genomic LOH (Clovis, data on file). Allowing prior treatment 
with a PARP inhibitor for the ovarian cancer patients reflects evolving treatment patterns and 
provides for the evaluation of possible restoration of sensitivity to PARP inhibition imparted 
by this combination. 
 Treatment Arm B Study Design 
Treatment Arm B of this study will investigate the safety, tolerability, PK, and efficacy of the 
PARP inhibitor, rucaparib, in combination with the ADC, sacituzumab govitecan (IMMU-
132).  
As described in Section 3.1, the treatment arm will consist of 2 phases: Phase 1b is 
dose-escalation phase primarily to determine the MTD and RP2D; and Phase 2 investigates 
the RP2D for the combination of rucaparib and sacituzumab govitecan in patients with 
prespecified tumor types. 
For patients enrolled into Treatment Arm B (Phase 1b or Phase 2) of the study, patients will 
receive oral rucaparib BID continuously and IV sacituzumab govitecan on Days 1 and 8 of 
21-day cycles. 
8.B.4.1 
Treatment Arm B: Screening and Enrollment 
All patients will undergo screening assessments, including disease status per RECIST v1.1, 
prior to enrollment, within the time frame specified by the Schedule of Assessments 
(Table 8.B-6). In addition to the tumor tissue collection for genomic analysis, Trop-2 
expression analysis will also be conducted.  
Treatment Arm B will enroll patients who have met all of the inclusion criteria and none of 
the exclusion criteria presented in Section 8.B.5.2 and Section 8.B.5.3. The criteria may be 
different depending upon which phase of Treatment Arm B the patient is enrolled; these 
phase-specific criteria are indicated, as appropriate. 
Phase 1b will enroll adult patients with previously-treated, locally-advanced unresectable or 
metastatic TNBC; previously-treated locally-advanced, or metastatic UC; or relapsed, 
platinum-resistant ovarian cancer. Patients with an advanced, recurrent, or metastatic solid 


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tumor with documented evidence of a deleterious alteration in BRCA1, BRCA2, PALB2, 
RAD51C, and/or RAD51D are also eligible for the Phase 1b portion of the study.  
Phase 2 will enroll patients into 1 of 3 cohorts: 
Cohort B1: 
Patients with locally-advanced unresectable or metastatic TNBC 
Cohort B2:  Patients with locally-advanced or metastatic UC 
Cohort B3: 
Patients with relapsed, platinum-resistant ovarian cancer  
 
Patients enrolled into Cohort B1 will have a diagnosis of either locally advanced unresectable 
or metastatic TNBC refractory to or relapsing after at least 1 prior standard-of-care 
chemotherapy regimen for unresectable, locally advanced or metastatic breast cancer. Phase 
2 patients may have received no more than 3 prior therapies. Earlier adjuvant or neoadjuvant 
treatment for more limited disease will qualify as one of the prior regimens if the 
development of unresectable, locally advanced or metastatic disease occurred within 
12 months of adjuvant therapy. Eligible patients will have received prior treatment with a 
taxane in either the adjuvant or metastatic setting. 
Patients enrolled into Cohort B2 will have locally advanced or metastatic UC and will have 
received 1 or 2 prior standard of care treatment regimens (eg, cisplatin- or carboplatin-
containing chemotherapy and/or immune checkpoint inhibitor) for advanced or metastatic 
disease. 
Patients enrolled into Cohort B3 will have relapsed, high-grade serous or Grade 2 or Grade 3 
endometrioid epithelial ovarian, fallopian tube or primary peritoneal cancer that is resistant 
(progression-free interval < 6 months after their last dose of platinum) to the most recently 
administered platinum-based therapy. These patients will have received ≤ 1 line of treatment 
for platinum-resistant disease. 
8.B.4.2 
Treatment Arm B: Treatment Phase 
For both Phase 1b and Phase 2 of Treatment Arm B, patients will visit the study site on 
Day 1, Day 8, and Day 15 of Cycle 1 and Cycle 2, and on Day 1 and Day 8 of every cycle 
thereafter (see Table 8.B-6).  
Patients will be assessed for disease status per RECIST v1.1 at screening, every 6 weeks 
(± 1 week) for the first 24 weeks, and then every 9 weeks (± 1 week) thereafter until 
radiological disease progression as assessed by the investigator, death, loss to follow-up, 
withdrawal from study, or study termination, or initiation of subsequent anticancer 
treatments. Responses (CR or PR) identified prior to 24 weeks will be confirmed at the next 
scheduled scanning timepoint (6 weeks later). For responses identified after 24 weeks, 
confirmatory scans should be obtained no less than 4 weeks after the initial response. 


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8.B.4.2.1 
Phase 1b 
Phase 1b is based on a standard 3+3 design as described in Section 3.1.3.1. The first dose of 
combination study treatment (rucaparib and sacituzumab govitecan) will be administered on 
Day 1 of Cycle 1. The first 21 days of study treatment (Cycle 1) is the DLT-evaluation 
period. During the DLT-evaluation period, patients will come into the study site for a visit on 
Day 1, Day 8, and Day 15. 
The initial combination dose consists of oral rucaparib 300 mg BID, administered 
continuously, in combination with IV sacituzumab govitecan 6 mg/kg administration on 
Days 1 and Day 8 of a 21-day cycle. The dose of rucaparib will be escalated in 100 mg BID 
increments up to a maximum of 600 mg BID. The dose of sacituzumab govitecan will be 
escalated in increments of 2 mg/kg, up to a maximum dose of 10 mg/kg. Once the initial dose 
has been evaluated for the first cohort and deemed safe and tolerable, parallel cohorts, where 
the dose of 1 investigational agent remains the same as in the prior cohort while the dose of 
the other agent is escalated, may be evaluated going forward. For example, a cohort receiving 
400 mg BID rucaparib in combination with 6 mg/kg sacituzumab govitecan may be 
evaluated in parallel with a separate cohort receiving 300 mg BID rucaparib in combination 
with 8 mg/kg sacituzumab govitecan. Doses of rucaparib and/or sacituzumab govitecan less 
than 300 mg BID and 6 mg/kg IV, respectively, may be evaluated based on unacceptable 
toxicity observed at the initial dose cohort.  
Prior to initiating treatment at each new combined dose level or prior to expanding an 
existing dose level, a safety teleconference will be held to review patient data, including but 
not limited to demographics, PK results (if available), study drug combination dosing, 
concomitant medications, hematology and chemistry, and AEs, and then confer and 
document agreement that dose escalation and/or expanding an existing dose level is/are 
considered appropriately safe. Safety teleconferences will include study investigators, the 
sponsor’s medical monitor, and may include other representatives or designees of the sponsor 
and the study sites. 
Dose modifications will be made based on clinical judgement and the dose modification 
guidance provided in Section 8.B.6.4. 
8.B.4.2.1.1 
Dose-limiting Toxicity Criteria 
A DLT considered for dose escalation in Phase 1b of Treatment Arm B is defined as any of 
the following occurring within the first 21 days of initiating combination treatment (Cycle 1) 
that is assessed by the investigator as possibly related to rucaparib and/or sacituzumab 
govitecan (refer to Section 10.7.4 for consideration of causal relationship). Where applicable, 
event will be assessed, according to the NCI CTCAE v5.0. 
• Grade 3 or greater febrile neutropenia (ie, fever > 38.3°C with ANC < 1.0 × 109/L) of any 
duration; 
• Grade 3 or 4 neutropenia lasting more than 7 days despite GCSF administration; 


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• Grade 3 thrombocytopenia (platelets < 50 × 109/L) with significant bleeding or Grade 4 
thrombocytopenia (platelets < 25 × 109/L) ≥ 5 days duration; 
• Grade 4 anemia (ie, life-threatening consequences; urgent intervention indicated) or any 
anemia (regardless of grade or severity) requiring a blood transfusion; 
• Any nonhematological AE ≥ Grade 3, with the exception of: 
- 
Nausea, vomiting, and diarrhea if well controlled by systemic medication and with 
duration ≤ 48 hrs; 
- 
Fatigue; 
- 
Grade 3 ALT or AST not accompanied by a concomitant increase in total bilirubin 
above the ULN. Note: any Grade 4 ALT/AST is a DLT. 
• Any Grade 3 or greater infusion-related reaction that fails to resolve within 4 hours 
despite optimal medical management.  
 
If a patient is not evaluable for a DLT, then an additional patient may be enrolled. For the 
definition of evaluability, please refer to Section 9.2.  
8.B.4.2.1.2 
RP2D Selection and Expansion 
As described in Section 3.1.3.1.2, once the RP2D of the combination has been provisionally 
established, up to 10 additional patients may be enrolled and treated in Phase 1b, in order to 
further characterize safety, tolerability, and PK and confirm that this is the optimal dose 
combination to evaluate in the Phase 2 portion.  
8.B.4.2.1.3 
Phase 1b – Cycle 2 and Beyond 
Following the DLT-evaluation period, patients will come into the study site for a visit on 
Day 1, Day 8 and Day 15 of Cycle 2, and on Days 1 and 8 of every cycle thereafter. Patients 
will be monitored for safety, PK, and efficacy as outlined in the Schedule of Assessments 
(Table 8.B-6) and PK Assessments (Table 8.B-7). 
After the 21-day DLT-evaluation period, recommendations for rucaparib and sacituzumab 
govitecan dose modification for the management of specific AEs are provided in 
Section 8.B.6.4. 
Patients tolerating the investigational treatment(s) at the assigned dose combination for at 
least 4 cycles may be permitted to escalate to the next highest combination dose regimen as 
long as the new dose regimen is lower than that being currently evaluated for safety and 
tolerability and/or the dose level is the same or lower than that determined to be the RP2D. 
All individual patient dose-escalation steps must be approved by the study’s medical 
monitor.  
Patients will be treated until disease progression, unacceptable toxicity, patient or 
investigator request to discontinue, death, initiation of any other anticancer therapy, positive 
pregnancy test, or termination of the study (Section 3.2). If a patient receiving study drug has 
met criteria for radiologic disease progression by RECIST v1.1 criteria but continues to 


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derive clinical benefit per the investigator, continuation of treatment may be permitted after 
discussion with the medical monitor (Section 5.9). 
8.B.4.2.2 
Phase 2 Cohort 
Upon determination of the RP2D from Phase 1b, Phase 2 will be initiated. In Phase 2, the 
selected RP2D from Phase 1b will be evaluated using Simon 2-stage designs in separate and 
parallel cohorts (see Section 8.B.9.1). Patients meeting all eligibility criteria will be enrolled 
into 1 of 3 cohorts as follows: 
Cohort B1: 
Patients with locally-advanced unresectable or metastatic TNBC 
Cohort B2:  Patients with locally-advanced or metastatic UC 
Cohort B3: 
Patients with relapsed, platinum-resistant ovarian cancer 
 
The Phase 2 cohorts were chosen due to the potential susceptibility to the combination of 
rucaparib and sacituzumab govitecan (Section 8.B.3.2).  
The RP2D of the combination of rucaparib and sacituzumab govitecan may be further 
adjusted, and/or alternative dosing schedules assessed during Phase 2 based on emerging 
safety, PK, and efficacy data.  
Patients will be monitored for safety, PK, and efficacy as outlined in the Schedule of 
Assessments (Table 8.B-6) and PK Assessments (Table 8.B-7). 
Dose modification guidelines in Section 8.B.6.4 should be followed throughout the Phase 2.  
Patients will be treated until disease progression, unacceptable toxicity, patient or 
investigator request to discontinue, death, initiation of any other anticancer therapy, positive 
pregnancy test, or termination of the study (Section 3.2). If a patient receiving study drug has 
met criteria for radiologic disease progression by RECIST v1.1 criteria but continues to 
derive clinical benefit per the investigator, continuation of treatment may be permitted after 
discussion with the medical monitor (Section 5.9).  
8.B.4.3 
End of Treatment Arm B and Safety Follow-up 
Upon treatment discontinuation, regardless of reason (with the exception of withdrawal of 
consent or death), patients will have an End of Treatment Visit, and assessments are specified 
for each treatment arm in the Schedule of Assessments within Table 8.B-6. All patients will 
be followed for at least 28 days after the last dose of study drug. Safety follow-up 
assessments are specified for Treatment Arm B in the Schedule of Assessment. 
 Study Population Selection for Treatment Arm B 
8.B.5.1 
Treatment Arm B: Number of Patients and Sites 
In Phase 1b, it is estimated that up to 55 patients will be enrolled, dependent upon the 
number of dose cohorts enrolled. 


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In Phase 2, up to 139 patients will be enrolled into the following cohorts: 
Cohort B1: 
Up to 53 patients with metastatic TNBC 
Cohort B2:  Up to 53 patients with locally-advanced or metastatic UC 
Cohort B3: 
Up to 33 patients with relapsed, platinum-resistant ovarian cancer  
 
Patients will enroll into either Phase 1b or Phase 2, but a patient cannot enroll into both 
phases of the same treatment arm. For Phase 2, patients will enroll across all cohorts based 
on separate Simon 2-stage designs for each cohort. Enrollment into Phase 2 for each cohort 
will continue until the required number of patients for each stage is reached (Section 8.B.9.1) 
The enrollment of the 2 phases in Treatment Arm B of the study is up to 194 patients. It is 
planned that 3 to 6 sites in the US are expected to participate in Phase 1b of the study; 
approximately 25 sites globally may be activated to participate in the Phase 2 portion of the 
study. 
8.B.5.2 
Treatment Arm B: Inclusion Criteria 
All patients participating in Treatment Arm B must meet all of the following inclusion 
criteria: 
1. Have signed an IRB/IEC-approved ICF prior to any study-specific evaluation; 
2. Be ≥ 18 years of age at the time the ICF is signed; 
3. Have an ECOG performance status of 0 or 1; 
4. Have a life expectancy greater than 3 months per investigator discretion; 
5. Has adequate organ function confirmed by the following laboratory values obtained 
within 14 days of the first dose of study drug: 
a. Bone Marrow Function: 
i. 
ANC ≥ 1.5 × 109/L; 
ii. 
Platelets > 100 × 109/L; 
iii. 
Hemoglobin ≥ 9 g/dL 
Note: All hematology values must be achieved without the need for transfusion or 
growth factors ≤ 14 days prior to the planned start of study treatment (C1D1);  
b. Hepatic Function 
i. 
AST and ALT ≤ 3 × ULN; if liver metastases, then ≤ 5 × the institutional ULN; 
ii. 
Total bilirubin ≤ 1.5 × institutional ULN; 
iii. 
Albumin ≥ 30 g/L (3.0 g/dL); 
c. Renal Function 
i. 
Creatinine ≤ 1.5 × institutional ULN OR estimated eGFR ≥ 45 mL/min using the 
Cockcroft-Gault formula (Appendix 1); 


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ii. 
Less than or equal to 1+ proteinuria. Patients with > 1+ proteinuria on dipstick 
must perform a 24-hour urine collection demonstrating ≤ 1.0 g over 24 hours; 
6. Have measurable disease per RECIST v1.1; 
7. Women of childbearing potential must have a negative serum or plasma pregnancy test 
within 3 days prior to administration of the first doses of study drug; 
8. Have sufficient archival or more recently obtained FFPE tumor tissue available for 
genomic analyses (refer to Section 7.5.1); 
9. For Phase 1b and Phase 2, has 1 of the following 4 diagnoses (a through d): 
a. TNBC histologically- or cytologically-confirmed by immunohistochemistry (IHC) or 
fluorescence in situ hybridization (FISH), and 
i. 
Is refractory to or has relapsed following 1 to 3 prior standard of care 
chemotherapy regimens for unresectable, locally advanced, or metastatic disease. 
Earlier adjuvant or neoadjuvant treatment for more limited disease will qualify as 
one of the prior regimens if the development of unresectable, locally advanced, or 
metastatic disease occurred within 12 months of adjuvant therapy.  
Note: While patients participating in Phase 2 are limited to 3 prior regimens, 
patients participating in Phase 1b are allowed to have received more than 3 prior 
chemotherapy regimens. 
ii. 
Must have received a taxane, regardless of disease stage (adjuvant, neoadjuvant, 
or advanced) when it was given. Patients who have contra-indications or are 
intolerant to taxanes are eligible provided they received at least 1 cycle of a 
taxane and demonstrated intolerance or contra-indication during or at the end of 
that cycle of treatment. 
iii. 
Prior platinum (cisplatin or carboplatin, either as monotherapy or in combination) 
for advanced breast cancer is allowed, provided there was no evidence of disease 
progression during the platinum chemotherapy. 
iv. 
Prior platinum received as potentially curative treatment for a prior cancer (eg, 
ovarian cancer) or as adjuvant/neoadjuvant treatment for breast cancer is allowed, 
provided ≥ 12 months have elapsed between the last dose of platinum-based 
treatment and treatment with study drugs. 
v. 
Phase 2 only: must have received prior therapy with an anthracycline unless 
contraindicated or declined by the patient. 
vi. 
Phase 1b only: Patients with TNBC associated with a deleterious BRCA 
mutation must have received prior treatment with a PARP inhibitor (either 
olaparib or talazoparib). Phase 2 only: Patients with TNBC cannot have received 
prior treatment with a PARP inhibitor. 
b. Histologically or cytologically confirmed locally advanced (tumor, node, metastasis 
[TNM] staging of T4b and any N; or any T and N2-3) or metastatic transitional cell 
carcinoma of the urothelium (including renal pelvis, ureter, urinary bladder, or 
urethra). Mixed transitional/non-transitional cell histologies are allowed. 
i. 
Has received 1 or 2 prior standard of care treatment regimens (eg, cisplatin- or 
carboplatin-containing chemotherapy and/or immune checkpoint inhibitor) for 


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advanced or metastatic disease and had confirmed radiologic disease progression 
during or following the most recent treatment.  
Note: Patients participating in Phase 1b are allowed to have received more than 
2 prior chemotherapy regimens, including platinum. 
ii. 
Neoadjuvant or adjuvant treatment for muscle invasive disease will be considered 
a treatment regimen if radiologic disease progression occurred ≤ 12 months from 
the start of treatment. 
iii. 
No more than 1 prior platinum-containing chemotherapy regimen for advanced 
disease permitted. A change of platinum within the same regimen will be 
considered 1 prior platinum-containing chemotherapy. 
iv. 
Patients must have received platinum-based chemotherapy (cisplatin or 
carboplatin), if eligible, and treatment with a PD-1/PD-L1 inhibitor, if eligible. 
These agents may have been administered as 2 separate regimens or as 
1 combined regimen. 
v. 
Patients with transitional cell carcinoma of the urothelium are eligible regardless 
of BRCA-mutation status. Prior treatment with a PARP inhibitor is only allowed 
for those patients enrolled into the Phase 1b portion of the study. Patients in the 
Phase 2 portion of the study cannot have received prior treatment with a PARP 
inhibitor. 
c. Histologically confirmed diagnosis of high-grade serous or Grade 2 or Grade 3 
endometrioid epithelial ovarian, fallopian tube, or primary peritoneal cancer and 
relapsed or PD confirmed by radiology. 
i. 
Has received ≥ 2 prior chemotherapy regimens, was resistant to most recently 
administered platinum-based treatment (ie, disease progression < 6 months after 
last dose of platinum) and has received ≤ 1 treatment for platinum-resistant 
disease. 
ii. 
Must have received prior treatment with bevacizumab-containing chemotherapy 
for platinum-resistant disease OR not be eligible to receive bevacizumab in this 
setting due to prior exposure in an earlier treatment setting OR not currently be 
eligible for treatment with bevacizumab. 
iii. 
Patients with platinum-refractory disease, ie, disease that progressed during or 
within 4 weeks after completing last platinum-based treatment are excluded. 
iv. 
Has treatment-free interval of ≥ 6 months following the first chemotherapy 
regimen received. 
v. 
Patients with platinum-resistant disease are eligible regardless of BRCA-mutation 
status. Prior treatment with a PARP inhibitor is permitted but not required. 
10. For Phase 1b only: A previously-treated, advanced, recurrent, or metastatic solid tumor 
with documented evidence of a deleterious alteration in BRCA1, BRCA2, PALB2, 
RAD51C, and/or RAD51D from tissue or plasma ctDNA testing. 
 
8.B.5.3 
Treatment Arm B Exclusion Criteria 
Patients who meet any of the following criteria will be excluded from Treatment Arm B: 


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1. Unable to swallow oral study drug; 
2. Have an active second malignancy, ie, patient known to have potentially fatal cancer 
present for which he/ she may be (but not necessarily) currently receiving treatment; 
Note: Patients with a history of malignancy that has been successfully treated, with no 
evidence of active cancer for 3 years prior to enrollment, or patients with surgically-cured 
low-risk tumors, such as early stage cervical or endometrial cancer are allowed to enroll. 
Patients receiving anticancer hormonal therapy in the maintenance setting are allowed to 
enroll. 
3. Have received prior treatment with any PARP inhibitor, with the following exceptions: 
a. Patients participating in Phase 1b are permitted to have had prior treatment with a 
PARP inhibitor; 
b. Patients with TNBC associated with a deleterious BRCA mutation who are 
participating in Phase 1b must have received prior treatment with a PARP inhibitor 
(either olaparib or talazoparib); 
c. Ovarian cancer patients participating in Phase 2 are permitted to have had prior 
treatment with a PARP inhibitor; 
4. Have previously received treatment with irinotecan, topotecan, or any derivative in any 
formulation; 
5. Have a known history of MDS; 
6. Have symptomatic and/or untreated CNS metastases. Patients with asymptomatic, 
previously-treated CNS metastases are eligible provided they have been clinically stable 
(not requiring steroids for at least 8 weeks prior to first dose of study drug) and have had 
appropriate scans at the screening assessment; 
7. Have a history of Gilbert’s disease; 
8. Have a known history of unstable angina, myocardial infarction, or congestive heart 
failure present within 6 months of randomization or clinically significant cardiac 
arrhythmia (other than stable atrial fibrillation) requiring anti-arrhythmia therapy; 
9. Have a prior history of gastrointestinal perforation within 6 months of the first scheduled 
study drug dose; 
10. Have known HIV or AIDS-related illness, or history of chronic hepatitis B or C, with the 
exception of patients with sustained virologic response after completion of treatment for 
hepatitis C; 
11. Have active chronic inflammatory bowel disease (ulcerative colitis or Crohn’s disease) or 
hospitalization for bowel obstruction within 3 months prior to planned enrollment. 
12. Have received chemotherapy, radiation, gene therapy, angiogenesis inhibitors, or 
experimental drugs ≤ 14 days prior to the first scheduled dose of study drugs, OR 
antibody therapy or other immunotherapy ≤ 4 weeks prior to first scheduled dose of study 
drugs,  


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13. Have ongoing toxicity from prior cancer treatment ≥ Grade 2 by NCI CTCAE v5.0, 
except alopecia; additionally, ongoing Grade 2 peripheral neuropathy may be permitted 
with prior advanced approval from the sponsor; 
14. Have had nonstudy-related minor surgical procedures ≤ 5 days, or major surgical 
procedure ≤ 21 days, prior to first scheduled dose of study drug. In all cases, the patient 
must be sufficiently recovered and stable before treatment administration; 
Note: placement of a port, catheter or central line is considered study-related. 
15. For female patients of childbearing potential and all male patients, the following are 
exclusion criteria, as applicable: 
a. Refusal to use highly effective method of contraception or to practice true abstinence 
during treatment and for 6 months after the last dose of rucaparib study treatment. 
b. Pregnant or breast feeding.  
c. Women of childbearing potential must not be considering getting pregnant during the 
study and for 6 months following the last dose of study drug. 
d. Male patients who refuse to use condoms during sex during and up to 6 months after 
study treatment. Male patients must not make semen donations during treatment and 
for 6 months following the last dose of rucaparib. 
16. Have any serious or unstable concomitant systemic disorder incompatible with the 
clinical study (eg, substance abuse, psychiatric disturbance, or uncontrolled intercurrent 
illness including active infection, arterial thrombosis, and symptomatic pulmonary 
embolism). 
17. Have any other condition that may increase the risk associated with study participation or 
may interfere with the interpretation of study results, and, in the opinion of the 
investigator, would make the patient inappropriate for entry into the study. 
 
No waivers of these inclusion or exclusion criteria will be granted by the investigators, the 
sponsor, or its designee. 
8.B.5.4 
Patients or Partners of Patients of Reproductive Potential 
Refer to Section 4.1. 
 Study Treatment(s): Arm B 
Refer to Section 5 for rucaparib treatment. 
8.B.6.1 
Investigational Drug Product – Sacituzumab Govitecan 
Sacituzumab govitecan (also known as IMMU-132 and hRS7-SN38) is an IV formulation. 
Sacituzumab govitecan for IV administration will be supplied to the study sites by the 
sponsor. A brief description of sacituzumab govitecan is provided below with details in the 
Pharmacy Manual. 


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Table 8.B-1 Description of Sacituzumab Govitecan 
Drug Name 
Sacituzumab govitecan; IMMU-132; hRS7-SN38 
INN 
Sacituzumab govitecan 
Formulation: 
10 mg/mL is formulated in 25 mM MES buffer, pH 6.5, together with 
the other excipients (25 mM trehalose, 0.01% Polysorbate 80). It is 
then lyophilized and filled at 200 mg/vial. 
How Supplied 
50-mL clear colored glass vials containing 200 mg of sacituzumab 
govitecan as a sterile, non-pyrogenic powder. 
Storage Conditions 
The sterile, non-pyrogenic powder should be stored between 2 and 8°C 
(35.6-46.4°F). 
Since the formulated drug product contains no preservative, vials 
should be used only once and within 8 hrs of reconstitution. 
 
8.B.6.2 
Sacituzumab Govitecan Packaging and Labeling 
Sacituzumab govitecan will be supplied by the sponsor in 50-mL clear colored glass vials 
containing 200 mg of sacituzumab govitecan as a sterile, non-pyrogenic powder 
(Table 8.B-1). The vials and outer carton will be labeled according to national regulations for 
investigational products. 
Details with respect to packaging and labeling of sacituzumab govitecan for infusion are 
described in the Pharmacy Manual. 
8.B.6.3 
Preparation and Administration of Sacituzumab Govitecan 
8.B.6.3.1 
Preparation  
The refrigerated sacituzumab govitecan vial should be brought to room temperature, without 
heating, prior to reconstitution. Sacituzumab govitecan should be reconstituted with 0.9% 
sodium chloride (normal saline). The 200 mg of powder in each vial can be reconstituted 
with 20 mL of normal sterile saline (10 mg/mL). Only saline should be used for 
reconstitution as other buffers have not been studied in stability. The reconstituted solution 
should be gently shaken and allowed to dissolve for up to 15 minutes. Appropriate use of 
aseptic technique should be employed. 
Calculate the prescribed dose in mg based on the patient’s body weight at the beginning of 
EACH cycle (or more frequently for > 10% change in body weight or if required by 
institutional policy). 
After determining the amount of reconstituted sacituzumab govitecan that will be needed for 
the patient’s dose, the necessary amount of reconstituted sacituzumab govitecan should be 
withdrawn from the vial(s) and injected into a glass or plastic evacuated infusion container 
(bag) slowly and without shaking to minimize foaming of the contents. Dilution with normal 
saline should be accomplished so the final sacituzumab govitecan concentration range is 1.1 
to 3.4 mg/mL (total volume should not exceed 500 mL). A sample drug preparation chart for 
a 70-kg patient is provided in Table 8.B-2 with 200 mg/vials and 250 mL bags of normal 


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saline as the infusion container. The saline-reconstituted sacituzumab govitecan study drug is 
stable for up to 8 hrs at room temperature. 
Initiate the infusion within 1 hour of reconstitution/dilution. If infusion is delayed beyond 
1 hour, refrigerate at 2 to 8°C for no more than 8 hours from reconstitution/dilution prior to 
infusion. If refrigerated, allow the diluted solution to come to room temperature prior to 
administration. If infusion does not begin within 8 hours after reconstitution/dilution, dispose 
of the original preparation and prepare a new infusion bag by reconstitution and dilution from 
new vials. Discard any unused portion in the vial. The product does not contain a 
preservative. 
Any amount of reconstituted sacituzumab govitecan that is not used for patient 
administration must be discarded appropriately. 
Table 8.B-2 Sacituzumab Govitecan Preparation for 10 mg/kg Dosing 
(Assume 70-kg Patient) 
Total Dose needed 
700 mg 
(200 mg/vial) 
Vials required 
4 
Volume of saline to be used for reconstitution 
20 mL 
Volume after reconstitution of each vial with USP saline 
80 mL 
Volume withdrawn for Scheduled Dose 
70 mL 
Dilute with Normal Saline 
180 mL 
Total volume dispensed 
250 mL 
Final concentration 
2.8 mg/mL 
Abbreviations: USP = United States Pharmacopeia. 
 
It is preferable for both PK and non-PK study visit days (Day 1 or Day 8) for a patient to first 
dose with rucaparib or for the site staff to ascertain prior dosing of rucaparib (if taken at 
home prior to the visit), prior to initiation of the sacituzumab govitecan infusion. When 
predose PK samples are indicated for both study drugs (refer to Table 8.B-7), the patient 
should be reminded to hold their morning dose of rucaparib prior to the site visit. 
8.B.6.3.2 
Preventative Medications 
Infusion-related Reactions: For prevention of infusion-related reactions, premedication 
with antipyretics and H1 and H2 blockers should be administered before each sacituzumab 
govitecan infusion. Corticosteroids (hydrocortisone 50 mg or equivalent oral or IV) may be 
administered prior to subsequent infusions if the patient had experienced an infusion-related 
reaction with a previous infusion.  
Nausea, Vomiting: Sacituzumab govitecan is considered to be moderately emetogenic. 
Premedication with a 2-drug antiemetic regimen is recommended. If nausea and vomiting are 
persistent, a 3-drug regimen may be used, including a 5-HT3 inhibitor (ondansetron or 
palonosetron, or other agents according to local practices), an NK1-receptor antagonist 
(fosaprepitant), and dexamethasone (10 mg oral or IV). Anticipatory nausea can be treated 


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with olanzapine. Additional antiemetics, sedatives, and other supportive measures may also 
be employed as clinically indicated. 
8.B.6.3.3 
Vital Signs  
Vital signs (heart rate, systolic and diastolic blood pressure, respiratory rate, and body 
temperature) will be assessed prior to the first infusion of sacituzumab govitecan in Cycle 1 
and every 15 ± 5 minutes for the first hour and then every 30 minutes until completing IV 
administration, at completion, and then 30 minutes post infusion. In absence of significant 
changes, this may be reduced with subsequent doses to prior to infusion, at 30 minutes, and 
then at completion. 
8.B.6.3.4 
Intravenous Administration of Sacituzumab Govitecan 
Do not administer as an IV push or bolus. Sacituzumab govitecan is administered 
intravenously as a slow infusion as described below. 
IV access must be well established prior to initiating infusion. At the time of dosing, the IV 
line will be connected to an infusion container with the prepared volume of sacituzumab 
govitecan. Either gravity or an infusion pump may be used. Only normal saline should be 
used as the infusion base solution, since the compatibility of sacituzumab govitecan with 
other infusion diluents has not been examined. 
The initial infusion should proceed slowly. If vital signs remain stable and in the absence of 
infusion reactions, the infusion rate can be incrementally advanced following suggested 
guidelines given in Table 8.B-3, and following completion, the intravenous line should be 
flushed slowly with 20 mL normal saline and the end of infusion time recorded. In the event 
of infusion reactions or vital sign changes, the infusion rate may be slowed, interrupted or 
terminated, as considered appropriate by the managing physician. 
Table 8.B-3 Infusion Rate Guidelines for Patients Remaining Stable in 
Absence of Hypersensitivity or Infusion-related Events 
Infusion Rate 
Infusion #1 
Subsequent Infusions 
Initial rate (first 15 minutes) 
50 mg/hr, or less 
100 – 200 mg/hr 
Incremental rate 
(advance every 15-30 minutes) 
50 mg/hr 
100 – 200 mg/hr 
Maximum recommended rate 
500 mg/hr 
1000 mg/hr 
 
 
8.B.6.4 Dose Modification and Retreatment Criteria for Rucaparib 
and Sacituzumab Govitecan 
Toxicities should be managed with supportive care and with dose modification for each of 
the study drugs according to the attribution of causality for the toxicity based on investigator 
judgement and consultation with the sponsor as appropriate. A dose modification of 
rucaparib or sacituzumab govitecan is permitted, with the other dose remaining constant, if 


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the causality is believed to be related to 1 study drug but not the other. General management 
of specific AEs are described for the rucaparib and sacituzumab govitecan combination are 
provided in Table 8.B-4. Management of new or worsening pulmonary symptoms is 
described in Section 8.B.6.4.1. 
The protocol allows aggressive medical management of patients in order to avoid dose 
reduction and dose delay as much as possible. Growth factors should be initiated according 
to guidelines below and may be used prophylactically as clinically indicated. For patients 
who could be considered high risk for neutropenia (those who experienced febrile 
neutropenia or Grade 3-4 neutropenia with prior treatments), use of growth factors may be 
initiated early on and used prophylactically as early as Cycle 1, except during the DLT period 
for those patients participating in Phase 1b. 
At the discretion of the investigator, the dose of rucaparib and/or sacituzumab govitecan may 
be held and/or reduced for Grade 2 toxicity that is attributed to either rucaparib or 
sacituzumab govitecan alone, or in combination, and not adequately controlled by 
concomitant medications and/or supportive care. 
If any blood parameters remain clinically abnormal after 3 weeks of dose interruption, the 
patient should be referred for further evaluation, as clinically appropriate. For clinically 
significant hematology results, bone marrow analysis and blood cytogenetic analysis should 
be considered according to standard hematological practice. 
If a patient continues to experience the same toxicity despite multiple dose reduction steps to 
the lowest allowable dose, or if dosing with either study drug is interrupted for 
> 21 consecutive days (or if 2 consecutive infusions are missed) due to the toxicity, study 
treatment should be discontinued, unless otherwise agreed upon between the investigator and 
the sponsor. If either rucaparib or sacituzumab govitecan is interrupted for greater than 21 
days, the patient may be discontinued from the study (Section 8.B.6.4.3). 
 


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Table 8.B-4 Dose Modification and Retreatment Criteria for Rucaparib and Sacituzumab Govitecan 
Adverse Event including 
Laboratory Abnormalities 
Severity 
(CTCAE 
Grade) 
Rucaparib 
Sacituzumab Govitecan 
Treatment 
Interruption 
Re-treatment 
Dose 
Modification 
Treatment 
Interruption 
Re-treatment 
Dose 
Modification 
Non-hematological Events 
Adverse event or laboratory 
abnormality 
1 or 2 
Nonea 
N/A 
Nonea 
None 
N/A 
Nonea 
Nausea, vomiting, or 
diarrhea despite maximal 
systemic 
antiemetic/antidiarrheal 
medication administered in 
standard doses according to 
institutional guidelines. See 
Section 8.B.6.5 
3 or 4 
Hold dose 
≤ Grade 2 
1st occurrence: 
Same dosea 
2nd occurrence 
of same AE: 
Reduce doseb  
3rd occurrence 
of same AE: 
Discontinue 
Hold dose 
≤ Grade 2 
1st occurrence: 
25% reductionb  
2nd occurrence 
of same AE: 
50% reductionb  
3rd occurrence 
of same AE: 
Discontinue 
Grade 4 non-hematologic 
toxicity of any duration,  
OR 
Other ≥ Grade 3 non-
hematologic toxicity 
persisting >48 hours despite 
optimal medical 
management, 
OR 
At time of scheduled 
infusion, ≥ Grade 3 non-
hematologic toxicity, which 
has delayed dosing by 1 
week 
3 or 4 
Hold dose 
≤ Grade 2 
1st or 2nd 
occurrence of 
same AE: 
Reduce doseb  
3rd occurrence 
of same AE: 
Discontinue 
Hold dose 
≤ Grade 2 
1st or 2nd 
occurrence of 
same AE: 
Reduce doseb  
3rd occurrence 
of same AE: 
Discontinue 


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Table 8.B-4 Dose Modification and Retreatment Criteria for Rucaparib and Sacituzumab Govitecan 
Adverse Event including 
Laboratory Abnormalities 
Severity 
(CTCAE 
Grade) 
Rucaparib 
Sacituzumab Govitecan 
Treatment 
Interruption 
Re-treatment 
Dose 
Modification 
Treatment 
Interruption 
Re-treatment 
Dose 
Modification 
ALT/AST elevation  
(in the absence of other signs 
of liver dysfunction) 
3 
Continuation of 
dosing permitted 
provided total 
bilirubin is 
< ULN and ALP 
is < 3 x ULN; 
monitor LFTs 
weekly; 
Hold if levels do 
not decline to 
≤ Grade 2 within 
2 weeks or if 
levels increase 
≤ Grade 2 
1st or 2nd 
occurrence: 
Reduce doseb 
 
3rd occurrence: 
Discontinue 
Continuation of 
dosing permitted 
provided total 
bilirubin is 
< ULN and ALP 
is < 3 x ULN; 
monitor LFTs 
weekly; 
Hold if levels do 
not decline to 
≤ Grade 2 within 
2 weeks or if 
levels increase. 
If not recovered 
within 3 weeks: 
discontinue  
≤ Grade 2 
1st occurrence: 
25% reductionb 
2nd occurrence: 
50% reductionb 
3rd occurrence: 
Discontinue 
ALT/AST elevation 
4 
Hold; 
monitor LFTs 
weekly; 
≤ Grade 2 
1st or 2nd 
occurrence: 
Reduce doseb 
 
3rd occurrence: 
Discontinue 
Hold; 
monitor LFTs 
weekly; 
≤ Grade 2 
1st occurrence: 
25% reductionb 
2nd occurrence: 
50% reductionb 
3rd occurrence: 
Discontinue 
ALT or AST elevations 
(> 3 × ULN) AND 
total bilirubin elevation 
(> 2 × ULN) - suspected 
DILI [Section 10.9]23,24 
NA 
Holdc; 
monitor LFTs 
weekly; 
≤ Grade 1 (or 
baseline) 
Subject to 
investigation: 
reduce dosec 
If DILI is 
confirmed, 
treatment should 
be permanently 
Holdc; 
monitor LFTs 
weekly; 
≤ Grade 1 (or 
baseline) 
Subject to 
investigation: 
reduce dosec 
If DILI is 
confirmed, 
treatment should 
be permanently 


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Table 8.B-4 Dose Modification and Retreatment Criteria for Rucaparib and Sacituzumab Govitecan 
Adverse Event including 
Laboratory Abnormalities 
Severity 
(CTCAE 
Grade) 
Rucaparib 
Sacituzumab Govitecan 
Treatment 
Interruption 
Re-treatment 
Dose 
Modification 
Treatment 
Interruption 
Re-treatment 
Dose 
Modification 
discontinued 
discontinued  
Hematological Events 
Adverse event or laboratory 
abnormality 
1 or 2 
Nonea 
N/A 
Nonea 
None 
N/A 
Nonea 
Anemia 
≥ 3 
Hold dosed. 
≤ Grade 2 
Same or reduced 
dosea, c 
Hold dosed. 
≤ Grade 2 
Same or reduced 
dosea, c 
Severe neutropenia, 
Grade 4 neutropenia ≥7 days, 
OR 
Grade 3 febrile neutropenia  
(absolute neutrophil count 
<1000/mm3 and fever 
≥38.5°C), 
OR 
At time of scheduled 
infusion, ≥ Grade 3 
neutropenia which has 
delayed dosing by 1 week 
3 or 4 
Hold dose 
≤ Grade 2; 
Growth factors 
should be used as 
clinically 
indicated 
1st occurrence: 
Same dose and 
add GCSF  
2nd occurrence: 
Reduce doseb  
3rd occurrence: 
Discontinue 
Hold dose 
≤ Grade 2; 
Growth factors 
should be used as 
clinically 
indicated 
1st occurrence: 
Same dose and 
add GCSF  
2nd occurrence: 
25% reductionb  
3rd occurrence: 
Discontinue 
Severe neutropenia that fails 
to recover to ≤ Grade 2 
within 3 weeks 
3 or 4 
Hold dose 
Fails to recover 
to ≤ Grade 2 
within 3 weeks 
Discontinue  
Hold dose 
Fails to recover 
to ≤ Grade 2 
within 3 weeks 
Discontinue  


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Table 8.B-4 Dose Modification and Retreatment Criteria for Rucaparib and Sacituzumab Govitecan 
Adverse Event including 
Laboratory Abnormalities 
Severity 
(CTCAE 
Grade) 
Rucaparib 
Sacituzumab Govitecan 
Treatment 
Interruption 
Re-treatment 
Dose 
Modification 
Treatment 
Interruption 
Re-treatment 
Dose 
Modification 
At time of scheduled 
infusion, ≥ Grade 3 non-
neutropenic hematologic 
event which delays dose by 1 
week and fails to recover 
≤ Grade 2 
3 or 4 
Hold dose 
≤ Grade 2 
 
1st occurrence: 
Same dose  
2nd occurrence: 
Reduce doseb  
3rd occurrence: 
Discontinue 
Hold dose 
≤ Grade 2 
 
1st occurrence: 
Same dose  
2nd occurrence: 
25% reductionb  
3rd occurrence: 
Discontinue 
Abbreviations: AE = adverse event; ALT = alanine aminotransferase; AML = acute myeloid leukemia; ANC = absolute neutrophil count; AST = aspartate 
aminotransferase; BID = twice a day; CTCAE = Common Terminology Criteria for Adverse Events; LFT = liver function test; MDS = myelodysplastic 
syndrome; N/A = not applicable; ULN = upper limit of normal. 
a 
At the discretion of the investigator, the dose of rucaparib may be held and/or reduced for Grade 2 toxicity that is attributed to rucaparib and not adequately 
controlled by concomitant medications and/or supportive care. 
b 
For dose reductions see Table 8.B-5. 
c 
Evaluate patient for the presence of confounding factors, including malignant disease in the liver, co-administration of other suspect drugs, cholestasis, and 
viral or autoimmune hepatitis, that could have caused the laboratory abnormalities. Other laboratory investigations of liver function such as INR should be 
implemented as indicated. If no alternative cause is identified, study drugs must be permanently discontinued. Patients should be followed until all 
abnormalities have returned to normal, returned to baseline levels, or an alternative cause is found to explain the combination of the increased 
transaminases and total bilirubin. 
d 
If anemia CTCAE Grade ≥3 persists for > 14 consecutive days, or a dependence upon blood transfusions occurs, then weekly complete blood counts 
should be performed until resolution of the event. If after 42 days of interruption and anemia has not improved to CTCAE Grade ≤ 1, the patient should be 
referred to hematologist and analysis of the bone marrow with cytogenetic studies and recommended according to standard practice. Bone marrow analysis 
should include a bone marrow aspirate (for cellular morphology, cytogenetic analysis, and flow cytometry) and a core biopsy (for bone marrow 
cellularity). 


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8.B.6.4.1 
Management of New or Worsening Pulmonary Symptoms 
If new or worsening unexplained pulmonary symptoms suggestive of pneumonitis 
(including, but not limited to, dyspnea) occur, or a deterioration of pulmonary function is 
observed, and/or radiologic abnormality is detected in the lungs, and this occurs in the 
absence of any clear diagnosis, a diagnostic workup (including high resolution computed 
tomography [CT] scan) in consultation with a pulmonologist should be performed in order to 
rule out pneumonitis. During this time, treatment with rucaparib may be interrupted or 
continued per investigator discretion. Sacituzumab govitecan treatment may also be 
interrupted or continued per investigator discretion. The contribution of sacituzumab 
govitecan should be assessed independently. 
Following investigation, if pneumonitis is not confirmed, treatment may be 
resumed/continued as deemed appropriate by the investigator and in accordance with the 
study protocol directions for management of AEs. All confirmed events of pneumonitis 
should be treated as appropriate per medical judgement and institutional guidelines. If the 
event resolves and retreatment is being considered, please consult the study Medical Monitor. 
Retreatment may be resumed at the current or a reduced dose, if appropriate.  
Refer to Section 10.7 and Section 10.8 of the protocol for additional information regarding 
classification and reporting of pneumonitis (and similar events, ie, interstitial lung disease, 
pulmonary fibrosis, acute interstitial pneumonitis, alveolitis necrotizing, alveolitis, 
hypersensitivity pneumonitis, and organizing pneumonia) as an AESI. 
8.B.6.4.2 
Rucaparib and/or Sacituzumab Govitecan Dose Reduction 
Potential dose reduction steps for rucaparib and sacituzumab govitecan based on different 
current doses are shown in Table 8.B-5. Rucaparib and sacituzumab govitecan dose 
reductions will occur in step-wise sequence. Doses lower than rucaparib 300 mg BID are not 
permitted without consultation with the medical monitor, and doses lower than sacituzumab 
govitecan 3 mg/kg are not permitted. 
Table 8.B-5 Rucaparib and Sacituzumab Govitecan Dose Reductions 
Rucaparib 
Sacituzumab Govitecan 
Current Dosage 
Dose Reductiona 
Current Dosage 
Dose Reductiona 
25% 
50% 
600 mg BID 
500 mg BID 
10 mg/kg 
7.5 mg/kg 
5 mg/kg 
500 mg BID 
400 mg BID 
8 mg/kg 
6 mg/kg 
4 mg/kg 
400 mg BID 
300 mg BID 
6 mg/kg 
4.5 mg/kg 
3 mg/kg 
300 mg BID 
200 mgb BID 
- 
- 
 
Abbreviations: BID = twice a day; QD = once a day. 
a 
No more than 2 dose reductions for the same AE are allowed for either study drug, after which treatment 
with both study drugs will be discontinued. 


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Table 8.B-5 Rucaparib and Sacituzumab Govitecan Dose Reductions 
Rucaparib 
Sacituzumab Govitecan 
Current Dosage 
Dose Reductiona 
Current Dosage 
Dose Reductiona 
25% 
50% 
b 
Consult with sponsor’s medical monitor before reducing the dose of rucaparib to this level. 
 
8.B.6.4.3 
Rucaparib and/or Sacituzumab Govitecan Discontinuation 
Rucaparib and sacituzumab govitecan should be permanently discontinued for any of the 
following: 
• If a patient continues to experience toxicity despite dose reduction steps to the lowest 
permissible dose for either study drug (see Table 8.B-5) or if dosing with either study 
drug is interrupted for > 21 consecutive days due to toxicity, treatment with both study 
drugs should be discontinued, with the following exceptions: 
- 
Treatment interruption > 21 days may be allowed if approved by the sponsor. Prior to 
re-initiating treatment for a patient with a treatment interruption lasting > 21 days, the 
study medical monitor/designee must be consulted. Tumor assessments should 
continue as per protocol even if treatment is interrupted. 
• Confirmed diagnosis of MDS/AML; 
• Any AE, laboratory abnormality, or intercurrent illness which, in the judgment of the 
investigator, presents a substantial clinical risk to the patient with continued study 
treatment dosing; or 
• Patient with progressive disease. If a patient receiving study drug has met criteria for 
radiologic disease progression by RECIST v1.1 criteria but continues to derive clinical 
benefit per the investigator, continuation of treatment may be permitted after discussion 
with the sponsor (Section 5.9). 
 
8.B.6.5 
Management of Adverse Events Specific to Sacituzumab Govitecan 
8.B.6.5.1 
Infusion-related Reactions 
Infusion-related reactions are defined as symptoms that occur during and within the first 
6 hours after the infusion of sacituzumab govitecan. Symptoms can include: fever, chills, 
rigors, arthralgias, myalgias, urticaria, pruritus, rash, diaphoresis, hypotension, dizziness, 
syncope, hypertension, dyspnea, cough, and wheezing, as well as severe hypersensitivity 
reactions including anaphylactic reactions. Infusion-related reactions should be treated in 
accordance with best clinical practices and standard institutional guidelines. Because of the 
potential for life-threatening infusion-related reactions, sacituzumab govitecan should only 
be administered in a setting in which appropriately trained medical staff, emergency 
equipment and medications are available in the event that resuscitation is required. NCI 


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CTCAE v5.0 is used to grade the severity of all infusion related AEs. Premedication for the 
prevention of infusion-related reactions is described in Section 8.B.6.3.2. 
Grade 3 and Grade 4 Events 
Grade 3 and Grade 4 infusion-related reactions can include severe or clinically significant 
cardiopulmonary events and severe allergic reactions such as symptomatic bronchospasm 
and anaphylactic reactions. Grade 3 infusion-related reactions are defined as those which are 
prolonged and do not improve with symptomatic treatment and/or brief interruption of 
treatment, reactions that recur following treatment, and reactions that require hospitalization. 
Grade 4 reactions include potentially life-threatening reactions, requiring urgent intervention. 
Severe allergic and anaphylactic reactions should be treated in accordance with best clinical 
practices and standard institutional guidelines. If Grade 3 or Grade 4 infusion-related 
reactions occur, sacituzumab govitecan should be permanently discontinued. 
Grade 2 Events 
Grade 2 infusion-related reactions are defined as those that require infusion interruption and 
respond to symptomatic treatment; prophylactic medications are indicated for ≤ 24 hours. For 
Grade 2 infusion-related reactions, the infusion should be interrupted for at least 15 minutes 
until symptoms resolve. After symptoms resolve, the infusion should be resumed at a slower 
infusion rate. Recommended infusion rates are provided in Table 8.B-3. For recurrent 
Grade 2 infusion reactions that fails to recover within 6 hours, despite optimal management, 
permanently discontinue sacituzumab govitecan. 
8.B.6.5.2 
Nausea, Vomiting, and Diarrhea 
Nausea, vomiting, and diarrhea are frequent sacituzumab govitecan-associated toxicities. 
Appropriate treatment, including, as needed, fluid and electrolyte replacement, is required to 
minimize the risk of serious consequences such as dehydration. Instructions for sacituzumab 
govitecan dose reduction for treatment-related gastrointestinal toxicities are provided in 
Section 8.B.6.4. 
Nausea and Vomiting 
Instructions for the use of premedications for prophylactic treatment of nausea and vomiting 
and anticipatory nausea are provided in Section 8.B.6.3.2. Do not hold the dose of 
sacituzumab govitecan for Grade 3 nausea unless Grade 3 nausea persists despite maximal 
optimal medical management (see Table 8.B-4). Patients should be treated for delayed 
nausea and vomiting on Days 2 and 3 with 5-HT3 receptor antagonist (ondansetron or 
palonosetron) monotherapy and other agents if needed. Steroids may be added if symptoms 
do not resolve with these other agents. Consider olanzapine for persistent or anticipatory 
nausea; an olanzapine dose of 2.5 mg or 5 mg at bedtime is recommended.  
Diarrhea   
Dietary modification should be recommended for the management of diarrhea, including a 
bland diet, small frequent meals, adequate fluid intake of clear liquids to maintain hydration, 


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and discontinuation of lactose-containing foods and drinks and alcohol. Loperamide should 
be administered at the onset of treatment-related Grade 1 or Grade 2 diarrhea, at an initial 
dose of 4 mg, followed by 2 mg with every episode of diarrhea to a maximum dose of 
16 mg/day. If diarrhea is not resolved after 24 hours, add diphenoxylate/atropine. 
If diarrhea persists, add octreotide 100 to 150 mcg subcutaneous three times per day. For 
Grade 3 or Grade 4 diarrhea, the patient should be hospitalized and treated with IV fluids and 
octreotide. Antibiotics can be administered as clinically indicated.  
Patients who exhibit an excessive cholinergic response to treatment with sacituzumab 
govitecan (eg, abdominal cramping, diarrhea, salivation) can receive appropriate 
premedication (eg, atropine) for subsequent treatments. 
8.B.6.5.3 
Neutropenia 
Complete blood cell counts must be obtained prior to each sacituzumab govitecan infusion 
and should be administered if absolute neutrophil counts (ANC) meet the following criteria: 
• Day 1: ANC > 1500/mm3 
• Day 8: ANC > 1000/mm3 
 
The routine prophylactic use of growth factors is not recommended; however, they may be 
used in patients who have experienced febrile neutropenia or Grade 3 or Grade 4 neutropenia 
following previous infusions. Growth factors may also be administered in the setting of 
neutropenia in patients at high risk of poor clinical outcomes, including those with prolonged 
neutropenia, ANC <100/mm3, febrile neutropenia, and serious infections. 
During the DLT-evaluation phase (Cycle 1 for patients in Phase 1b), transfusions may not be 
used as prophylaxis and should only be used to treat cytopenia considered to be 
dose-limiting. 
8.B.6.6 
Treatment Arm B Study Drug Compliance and Accountability 
Rucaparib treatment compliance is described in Section 5.7. Study drug accountability is 
described in Section 5.8. 
Each dose of IV sacituzumab govitecan will be prepared by a pharmacist or authorized 
designee and transferred to an infusion set, in accordance with the protocol and applicable 
local safe handling procedures. The IV infusion will be monitored by the investigator or 
designee. Treatment compliance will be monitored by drug accountability, and any 
preparation of infusion deviations (refer to Section 8.B.6.3.4) will be recorded on the 
patient’s eCRF. 


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 Prior and Concomitant Therapy 
See Section 6 for prior and concomitant therapy restrictions and information that is general 
across all treatment arms of this study. Additional information specific to the rucaparib and 
sacituzumab govitecan combination arm are described in this section. 
See Section 8.B.6.3.2 regarding premedication prior to infusion of sacituzumab govitecan for 
prevention of infusion reaction. 
8.B.7.1 
Immunosuppressive Agents 
With the exception of the preventative medication described in Section 8.B.6.3.2, 
immunosuppressive agents are prohibited. However, inhaled or topical steroids, and adrenal 
replacement steroid doses of up to 20 mg daily prednisone equivalent, are permitted in the 
absence of active autoimmune disease. Patients are permitted the use of topical, ocular, intra 
articular, intranasal, and inhalational corticosteroids (with minimal systemic absorption). 
Adrenal replacement steroid doses of up to 20 mg daily prednisone are permitted. A brief 
(less than 3 weeks) course of corticosteroids for prophylaxis (eg, contrast dye allergy) or for 
treatment of non-autoimmune conditions (eg, delayed-type hypersensitivity reaction caused 
by a contact allergen) is permitted. 
Patients with a condition requiring systemic treatment with either corticosteroids (> 10 mg 
daily prednisone equivalent) or other immunosuppressive medications within 14 days of 
treatment assignment are excluded. 
8.B.7.2 
Other Concomitant Medications 
Patients may be medicated during treatment with sacituzumab govitecan as indicated in the 
judgment of the treating physician to control potential infusion or hypersensitivity responses 
(see Section 8.B.6.3.2). For anaphylactic reactions, appropriate medical measures (eg, 
epinephrine, antihistamines, hydrocortisone, and IV fluids) should be taken. Such a patient 
should not receive additional sacituzumab govitecan and should be discontinued from the 
study. 
As described in Section 8.B.6.5.3, patients receiving sacituzumab govitecan who experience 
neutropenia will be prescribed growth factors as clinically indicated, including 
prophylactically. Other hematopoietic growth factors or blood transfusions are allowed at 
physician’s discretion. During the DLT-evaluation phase (Cycle 1 for patients in Phase 1b), 
transfusions may not be used as prophylaxis and should only be used to treat cytopenia 
considered to be dose-limiting. 
 Study Procedures and Methods for Treatment Arm B 
8.B.8.1 
Schedule of Assessments: Treatment Arm B 
Table 8.B-6 summarizes the procedures and assessments to be performed for all patients in 
Treatment Arm B (Phase 1b and Phase 2).  


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Table 8.B-7 summarizes the timing of collection of PK and immunogenicity samples for all 
patients in Treatment Arm B.  
The investigator or their designee shall discuss with each patient the nature of the study and 
its requirements. To participate in the study, written informed consent must be obtained from 
each potential patient prior to any study activities (see Section 11.2). The information on the 
IRB/IEC-approved consent form should be translated and communicated in the language the 
patient (or legally authorized representative) can understand.  
The screening period begins with the first study-specific procedure, performed outside 
standard of care, and only after written consent for study participation has been provided. 
Additionally, patients participating in the optional tumor tissue biopsy at the time of 
radiologic disease progression/treatment discontinuation must provide additional written 
consent for this procedure.  
All procedures and assessments are to be completed within ± 3 days of the scheduled time 
unless otherwise stated. 
 


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Table 8.B-6 Schedule of Assessments for All Patients in Treatment Arm B (Phase 1b and Phase 2) 
 
Screening Phase 
Treatment Phase 
(21-day cycles ± 3 days) 
Post Treatment Phase 
 
Cycles 1 and 2 
Cycles 3+ 
 
Study Day 
Day -56 
to 
Day -1 
Day -21 
to 
Day -1 
Day -14 
to 
Day -1 
Day 1 
Day 8 
Day 15 
Day 1 
Day 8 
End of 
Treatment 
28-day 
Safety FUa 
Procedureb 
 
Informed Consent 
X 
 
 
 
 
 
 
 
 
 
Medical/Oncology History (Section 7.1) 
X 
 
 
 
 
 
 
 
 
 
Tumor Tissue Sample (Section 7.5.1 and 
Section 8.B.8.2.1)c 
X 
 
 
 
 
 
 
 
 
 
Physical Examination (Section 7.4.5) 
 
X 
 
X 
 
 
X 
 
X 
X 
Vital Signs (Section 7.4.3 and 
Section 8.B.6.3.3)d 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
12-lead ECG (Section 7.4.4) 
 
X 
 
X 
 
 
X 
 
X 
 
Prior/Concomitant 
Medications/Procedures (Section 7.2)e 
 
X 
 
X 
X 
X 
X 
 
X 
X 
Disease Assessment/Tumor Scansf 
(Section 7.3.1) 
 
X 
 
 
 
 
X 
 
X 
 
ECOG Performance Status 
 
X 
 
X 
 
 
X 
 
X 
X 
Hematology (Section 7.4.2) 
 
 
X 
X 
X 
X 
X 
 
X 
X 
Chemistry (Section 7.4.2) 
 
 
X 
X 
X 
X 
X 
 
X 
X 
Urinalysis (Section 7.4.2) 
 
 
X 
 
 
 
 
 
 
 
Serum or plasma Pregnancy Test 
(WOCBP only) (Section 7.4.2) 
 
 
X 
X 
 
 
X 
 
X 
 
CA-125 Measurement for OC patientsg 
(Section 7.3.1) 
 
 
X 
X 
 
 
X 
 
X 
 
Pharmacogenomics Blood Sample 
(Section 7.5.3)h 
 
 
 
X 
 
 
 
 
 
 


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Table 8.B-6 Schedule of Assessments for All Patients in Treatment Arm B (Phase 1b and Phase 2) 
 
Screening Phase 
Treatment Phase 
(21-day cycles ± 3 days) 
Post Treatment Phase 
 
Cycles 1 and 2 
Cycles 3+ 
 
Study Day 
Day -56 
to 
Day -1 
Day -21 
to 
Day -1 
Day -14 
to 
Day -1 
Day 1 
Day 8 
Day 15 
Day 1 
Day 8 
End of 
Treatment 
28-day 
Safety FUa 
Procedureb 
 
Blood Sample for ctDNA Analysis 
(Section 7.5.2)i  
 
X 
 
X 
 
 
X 
 
X 
X 
Rucaparib Administrationj 
 
 
 
X 
X 
X 
X 
X 
 
 
Sacituzumab govitecan Administrationj 
 
 
 
X 
X 
 
X 
X 
 
 
Adverse Eventsk (Sections 10.7 and 
10.8) 
(X) 
(X) 
(X) 
X 
X 
X 
X 
X 
X 
X 
Post-progression Tumor Tissue Biopsy 
(Section 7.5.1)l 
 
 
 
 
 
 
 
 
X 
 
Blood Sample for PK (Phase 1b)  
Refer to Table 8.B-7 for sampling schedule 
 
Abbreviations: AML = acute myeloid leukemia; CA-125 = cancer antigen 125; ctDNA = circulating tumor deoxyribonucleic acid; ECG = electrocardiogram; 
ECOG = Eastern Cooperative Oncology Group; FU = Follow-up; MDS = myelodysplastic syndrome;  OC = ovarian cancer; PK = pharmacokinetics; 
WOCBP = women of child-bearing potential. 
a 
Follow-up Visit should occur 28 days (±7) from the last dose of study drug or can be performed on the date of discontinuation if that date is at least 28 days 
from last dose, whichever is later. Chemistry and hematology are only necessary at FU visit, if toxicities are present. The FU Visit should be conducted in 
person. 
b 
The study visit window in the treatment phase is ± 3 days, unless noted otherwise for a particular assessment. Study visits should take into account the 
patient’s investigational product supply. Only 1 cycle of oral study drug will be dispensed to the subject on Day 1 of each cycle. 
c 
The tumor tissue sample must be adequate for genomic testing. If archival tissue sample is inadequate or unavailable, a more recently obtained tissue 
sample will be required prior to enrollment. Refer to the Laboratory Manual for details on tissue adequacy, sample collection and handling instructions. 
d 
Vital signs should be assessed prior to the first infusion of sacituzumab govitecan in Cycle 1 and every 15 ± 5 minutes for the first hour and then every 
30 minutes until completing IV administration, at completion, and then 30 minutes post infusion. In absence of significant changes, this may be reduced 
with subsequent doses to prior to infusion, at 30 minutes, and then at completion. 


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e 
Patients taking warfarin should have INR monitored regularly per standard clinical practice (Section 6.5). Patients taking digoxin should have their digoxin 
levels monitored after starting rucaparib and then regularly per standard clinical practice (Section 6.6). 
f 
Disease assessments to consist of clinical examination and appropriate imaging techniques per RECIST v1.1 will occur every 6 weeks for the first 
24 weeks, and then every 9 weeks until radiological disease progression as assessed by the investigator, death, loss to follow-up, withdrawal from study, 
study termination. Other complementary studies may be performed if required. The same methods used to detect lesions at baseline are to be used to follow 
the same lesions throughout the clinical study. End-of-Treatment scans not required if disease progression determined and patient is not continuing study 
treatment.  
g 
CA-125 measurement should be performed for patients with ovarian cancer at screening and on Day 1 of every subsequent cycle, at treatment 
discontinuation, as clinically indicated. If a patient discontinues treatment for reasons other than disease progression, then a sample should be taken at the 
same time as radiological imaging and ctDNA sampling. 
h 
If sample is not collected on Day 1 of Cycle 1, it should be collected as soon as possible thereafter. 
i 
Day 1 of Cycle 1 through Cycle 6 and at the same time as radiological imaging and CA-125 sampling (for OC patients) thereafter, at the End of Treatment, 
and 28-day Follow-up Visit. If a patient discontinues treatment for reasons other than disease progression, then a sample should be taken at the same time 
as radiological imaging and CA-125 (for OC patients). 
j 
First dose of both study drugs in Cycle 1 should be administered within 3 days after enrollment. Rucaparib administration is continuous (not just the days 
specified in the table). Refer to Section 5.5 (rucaparib) and Section 8.B.6.3 (sacituzumab govitecan) for administration guidelines. Study treatment 
continues in 21-day cycles until disease progression, unacceptable toxicity, patient or physician request to discontinue, death, initiation of any other cancer 
therapy, positive pregnancy test, or termination of the study. For sacituzumab govitecan dosing, disease assessments (at the end of Cycles 2, 4, 6, 8, 10, and 
onward) must be completed and reviewed prior to the start of the next cycle. Rucaparib dosing is continuous unless interrupted or stopped for toxicity. 
k 
AEs, SAEs, and AESIs that occur after first administration of study drug through to 28 days after last dose of study drug(s). In addition, SAEs that were 
related to a screening procedure will also be recorded. Ongoing SAEs, AESIs, or treatment-related Grade 3/4 AEs will be followed to resolution or 
stabilization. After the Safety Follow-up, only SAEs considered as potentially study drug related (including serious reports of pneumonitis and similar 
events, ie, interstitial lung disease, pulmonary fibrosis, acute interstitial pneumonitis, alveolitis necrotizing, alveolitis, hypersensitivity pneumonitis, and 
organizing pneumonia, if considered to be related to study drug), and AESIs of MDS and AML, regardless of causality, will be recorded in the eCRF. 
l 
An optional tumor biopsy may be collected at or following disease progression until the start of the next treatment. Additional consent is required. Refer to 
the Laboratory Manual for details on sample collection and handling instructions. 
 
 
 


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Table 8.B-7 Pharmacokinetic and Immunogenicity Sample Collections in Treatment Arm B (Phases 1b and 2) 
Study Visit 
Sacituzumab govitecan PKa 
(All Phase 1b and Phase 2) 
Sacituzumab govitecan 
Immunogenicity 
(All Phase 1b and Phase 2) 
Rucaparib PK 
(All Phase 1b and Phase 2) 
Cycle 1 
D1 
 
Predoseb and 
30 min (±5 min) post EOI.  
Predoseb 
- 
D8 
 
Predoseb and 
30 min (±5 min) post EOI.  
- 
Predoseb  
Cycle 3, 5, 7  
D1 
 
Predoseb and 
30 min (±5 min) post EOI. 
Predoseb  
Predoseb 
D8 
 
Predoseb and 
30 min (±5 min) post EOI. 
- 
- 
Every 4 cycles after 
Cycle 7 (eg, 11, 15, etc) 
D1 
 
Predoseb and 
30 min (±5 min) post EOI. 
Predoseb 
- 
D8 
 
Predoseb and 
30 min (±5 min) post EOI. 
- 
- 
EOT Visit 
N/A 
X 
X 
- 
Safety Follow-up Visit 
 
X 
X 
- 
Abbreviations: D = Day; EOI = End of Infusion; EOT = End of Treatment; hrs = hours; N/A = not applicable; PK = pharmacokinetics. 
a 
Analyses of sacituzumab govitecan and metabolites (SN-38, SN-38G, Total SN-38, total antibody). 
b 
Predose refers to collection prior to the morning dose of both rucaparib and sacituzumab govitecan. For rucaparib, the predose should be collected within 
30 minutes before the morning dose. If the morning dose on the PK sampling day is on hold or delayed, the predose sample still needs to be collected at 
approximately 12 hours after the previous dose, if possible. For sacituzumab govitecan, the predose samples should be collected just prior to the 
administration from the contralateral arm (Section 8.B.8.2.4). 
Notes: Collection of the actual time(s) of dose administration on the day prior to the PK Visit (rucaparib only) and during the PK Visit (rucaparib and 
sacituzumab govitecan) is essential for PK assessment. 
Refer to the (Treatment Arm B) Laboratory Manual for details on sample handling and processing. 
 
 


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8.B.8.2 
Methods of Data Collection: Treatment Arm B 
See Section 7 for methods of data collection that are general across all treatment arms of this 
study. Additional information specific to the rucaparib and sacituzumab govitecan 
combination arm are described in this section. 
8.B.8.2.1 
Biomarker Analyses 
The tumor tissue collected for genomic analysis (see Section 7.5.1) will also be used to 
evaluate the expression of Trop-2 by IHC. The messenger RNA (mRNA) and/or protein 
levels of Trop-2 may also be evaluated using additional assays. 
8.B.8.2.2 
Pharmacokinetic and Immunogenicity Evaluations 
Samples for rucaparib and sacituzumab govitecan PK and immunogenicity assessments will 
be collected for all patients, as described in Table 8.B-7. For sacituzumab govitecan, 
corresponding serum samples designated for either PK or immunogenicity assessments may 
also be used for either of those analyses, if necessary (eg, insufficient sample volume to 
complete testing). If dosing is held for toxicity or any other reason on a PK Visit day, plasma 
samples for rucaparib PK and predose serum samples for sacituzumab govitecan PK and 
immunogenicity assessments should still be collected on the days and times specified in 
Table 8.B-7 and below. 
8.B.8.2.3 
Rucaparib Pharmacokinetic Sample Collection 
For all patients, plasma samples are to be collected for trough level PK analysis of oral study 
drug within 1 hour before the morning dose of rucaparib on Day 8 of Cycle 1 and Day 1 of 
Cycles 3, 5, 7, as described in Table 8.B-7. Plasma samples are to be collected approximately 
12 hours after the last oral dose, but prior to the next oral dose (ie, typically within 1 hour 
prior to dosing).  
A central laboratory will be used for bioanalysis of plasma rucaparib concentration 
measurement. Please refer to the Laboratory Manual for details on collection and processing 
of blood PK samples. 
8.B.8.2.4 
Sacituzumab govitecan Pharmacokinetic Sample Collection 
For all patients in Phase 1b and Phase 2, PK samples will be collected for sacituzumab 
govitecan predose and 30 minutes after the end of infusion on Day 1 and Day 8 of Cycles 1, 
3, 5, 7, and every 4 cycles thereafter (eg, Cycle 11, 15, etc.), as well as the End of Treatment 
Visit and Safety Follow-up Visit, as described in Table 8.B-7. 
All time points are relative to the start of IV treatment administration. All on-treatment time 
points are intended to align with days on which IV treatment is administered. If it is known 
that a dose is going to be delayed, then the predose sample should be collected just prior to 
the delayed dose. However, if a predose sample is collected but the IV dose is subsequently 
delayed, then an additional pre-dose sample should not be collected. 


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Blood samples should be drawn from a site other than the sacituzumab govitecan IV infusion 
site (ie, contralateral arm) on days of infusion. All samples collected predose should be 
collected just prior to the administration from the contralateral arm (ie, the arm not used for 
the infusion). If the infusion was interrupted, the interruption details will also be documented 
on the eCRF. Blood samples will be processed to collect serum and stored preferably 
at -70°C (samples may be stored at -20°C up to 2 months). Further details of PK sample 
collection and processing will be provided to the site in the Laboratory Guidelines. Serum 
concentration analyses for sacituzumab govitecan will be performed by validated 
bioanalytical method(s). 
8.B.8.2.5 
Sacituzumab govitecan Immunogenicity Assessments 
Samples for sacituzumab govitecan immunogenicity assessments will be collected for all 
patients predose on Day 1 Cycles 1, 3, 5, 7, and every 4 cycles thereafter (eg, Cycle 11, 15, 
etc), at the End of Treatment, and at the Safety Follow-up Visit, as described in Table 8.B-7. 
The serum samples will be analyzed for anti-sacituzumab govitecan drug antibodies (ADA) 
by validated immunoassays. Samples with a positive ADA response may also be analyzed for 
neutralizing ADA response to sacituzumab govitecan. The immunogenicity (and 
corresponding drug exposure) data from these samples will be reported as part of a patient’s 
overall immunogenicity assessment.  
Selected serum samples may be analyzed by an exploratory method that measure 
sacituzumab govitecan or detect ADA for technology exploration purposes; exploratory 
results will not be reported. Further details of immunogenicity sample collection and 
processing will be provided to the site in the Laboratory Manual. 
 Planned Statistical Methods: Treatment Arm B 
The statistical methods that are general across treatment arms are described within 
Section 9.  
The determination of sample size for Treatment Arm B, Phase 1b and Phase 2 cohorts are 
described below. 
8.B.9.1 
Determination of Sample Size 
The total enrollment planned for evaluation of rucaparib in combination with sacituzumab 
govitecan is up to 194 patients. 
Phase 1b is a standard 3+3 dose-escalation design and the overall sample size depends on the 
occurrence of safety findings, specifically, DLTs, observed at the different dose levels. Up to 
55 patients across all dose levels may be enrolled. Additional patients may be enrolled to 
evaluate other dose levels or schedules as described in Section 8.B.4.2.1. Additional patients 
may be enrolled into a particular dose cohort if a patient already enrolled into that same dose 
cohort does not meet the criteria for the DLT-evaluable Population, defined in Section 9.2. 


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A Simon 2-stage design will be used to evaluate efficacy (confirmed overall response of CR 
or PR) of rucaparib in combination with sacituzumab govitecan in each of the Phase 2 
cohorts. The sample sizes for each pre-specified tumor cohorts in Phase 2 were determined 
based on a null hypothesis (H0), which specifies a response proportion that if not reached 
(response is less than that specified), further investigation would not be warranted, and an 
alternative hypothesis (H1), which specifies a response proportion that if observed would 
warrant further investigation of the rucaparib and sacituzumab govitecan combination 
treatment in the corresponding cohort. 
Phase 2 Cohort B1: Patients with locally-advanced unresectable or metastatic TNBC 
Up to 53 patients (24 patients enrolled in Stage 1 and 29 patients enrolled in Stage 2) will be 
treated to assess efficacy. After the first 24 patients either a) complete 16 weeks of study 
treatment or b) discontinue study treatment prior to completing 16 weeks, an interim 
(Stage 1) analysis will be performed. If ≤ 7 of these 24 patients have a confirmed overall 
response (CR or PR per investigator assessment), the sponsor and key participating 
investigators will evaluate overall benefit:risk for patients and determine whether or not to 
continue further enrollment. If 8 or more patients in Stage 1 have a confirmed overall 
response, then enrollment of the additional 29 patients will be completed.  
Characteristics of this design include: 
• H0: p ≤ 0.30; 
• H1: p ≥ 0.50; and 
• 90% power at significance level = 0.05 (one-sided). 
 
If Stage 2 is fully enrolled and ≥ 22 out of 53 total patients have a confirmed overall 
response, then per the design, the null hypothesis is rejected, and the rucaparib and 
sacituzumab govitecan combination warrants consideration of further investigation in 
patients with metastatic TNBC. 
Phase 2 Cohort B2: Patients with locally-advanced or metastatic UC 
Up to 53 evaluable patients (24 patients enrolled in Stage 1 and 29 patients enrolled in 
Stage 2) will be treated to assess efficacy. After the first 24 patients either a) complete 
16 weeks of study treatment or b) discontinue study treatment prior to completing 16 weeks, 
an interim (Stage 1) analysis will be performed. If ≤ 7 of these 24 patients have a confirmed 
overall response (CR or PR per investigator assessment), the sponsor and key participating 
investigators will evaluate overall benefit:risk for patients and determine whether or not to 
continue further enrollment. If 8 or more patients in Stage 1 have a confirmed overall 
response, then enrollment of the additional 29 patients will be completed. 
Characteristics of this design include: 
• H0: p ≤ 0.30; 


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• H1: p ≥ 0.50; and 
• 90% power at significance level = 0.05 (one-sided). 
 
If Stage 2 is fully enrolled and ≥ 22 out of 53 total patients have a confirmed overall 
response, then per the design, the null hypothesis is rejected, and the rucaparib and 
sacituzumab govitecan combination warrants consideration of further investigation in 
patients with locally-advanced or metastatic UC. 
Phase 2 Cohort B3: Patients with relapsed, platinum-resistant ovarian cancer 
Up to 33 evaluable patients (22 patients enrolled in Stage 1 and 11 patients enrolled in 
Stage 2) will be treated to assess efficacy. After the first 22 patients either a) complete 
16 weeks of study treatment or b) discontinue study treatment prior to completing 16 weeks, 
an interim (Stage 1) analysis will be performed. If ≤ 2 of these 22 patients have a confirmed 
overall response (CR or PR per investigator assessment), the sponsor and key participating 
investigators will evaluate overall benefit:risk for patients and determine whether or not to 
continue further enrollment. If 3 or more patients in Stage 1 have a confirmed overall 
response, then enrollment of the additional 11 patients will be completed.  
Characteristics of this design include: 
• H0: p ≤ 0.10; 
• H1: p ≥ 0.30; and 
• 90% power and at significance level = 0.05 (one-sided). 
 
If Stage 2 is fully enrolled and ≥ 7 out of 33 total patients have a confirmed overall response, 
then per the design, the null hypothesis is rejected, and the rucaparib and sacituzumab 
govitecan combination warrants consideration of further investigation in patients with 
relapsed, platinum-resistant ovarian cancer.  
 
 


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8.C TREATMENT ARM C: RUCAPARIB AND M4344 
 Ataxia telangiectasia mutated and Rad3-related (ATR) Inhibition 
The protein kinase ataxia telangiectasia mutated and Rad3-related (ATR) is recruited to 
junctions of single-stranded and double-stranded DNA, which most commonly arises at sites 
of replication stress (RS). If left unresolved, this structure rapidly collapses to form a double-
strand break (DSB), which can lead to deleterious chromosomal rearrangements or cell death. 
RS occurs during S-phase when the cell’s DNA replication machinery encounters a fragile 
region of DNA or an unresolved lesion. Treatment of cells with DNA-damaging agents can 
lead to very high levels of RS as cells progress to S-phase without resolving damage incurred 
by such agents. The RS pathway is closely associated with a DSB repair pathway mediated 
by the protein kinase ataxia telangiectasia mutated (ATM)83 due to frequent interconversion 
of damaged structures within the cell and because the apical kinases, ATR and ATM, share 
many downstream substrates. It has been demonstrated that inhibition of ATR in response to 
RS can lead to activation of ATM and a compensatory DNA repair and survival response.84 
However, for many cancer cells, this compensatory pathway is not available, as ATM 
signaling is often defective. This most commonly arises from loss-of-function mutations in 
p53, a principal substrate for ATM, but can also occur from loss of ATM expression or 
defective activation of ATM.85-88 Such defects in ATM signaling can cause a dependence on 
ATR for survival from the RS caused by treatment with DNA-damaging agents.84,89-93 
Accordingly, it is expected that an ATR inhibitor will sensitize many cancer cells to the 
cytotoxic effects of various DNA-damaging agents. In contrast, noncancer cells have been 
shown to tolerate combinations of ATR inhibitors and DNA-damaging agents with just a 
transient increase in growth arrest.84 High levels of RS are evident in some cancer cells, even 
in the absence of a DNA-damaging agent resulting from expression of oncogenes that drive 
dysregulated replication, a hypoxic environment, or from defects in other repair pathways. 
This high RS in cancer cells can drive a reliance on ATR for survival and, accordingly, ATR 
inhibitors may have benefit as monotherapy.94-98 
 M4344 Background 
Overviews of data from nonclinical and clinical studies are provided below and described in 
detail in the M4344 IB. M4344 was initially developed under the name “VX 803” by Vertex 
Pharmaceuticals Incorporated. 
8.C.2.1 
Mechanism of Action of M4344 
M4344 is a potent ATR inhibitor with high selectivity over other kinases and sensitizes many 
human cancer cell lines to the cytotoxic effects of various DNA-damaging agents. ATR and 
its downstream kinase CHK1 checkpoint kinase 1 (CHK1), are activated by DNA replication 
stress and DNA damage, thereby arresting cell-cycle progression allowing time for 
appropriate damage repair and completion of replication. ATR/ CHK1 blockade prevents 
DNA damage-induced cell-cycle arrest, resulting in inappropriate entry into mitosis, 
chromosome aberrations, unequal partitioning of the genome, and ultimately apoptosis. 


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8.C.2.2 
Nonclinical Experience 
8.C.2.2.1 
Nonclinical Pharmacology 
M4344 is a potent and selective inhibitor of ATR kinase. In cellular assays, M4344 blocked 
ATR activity and showed single-agent cytotoxic activity against some cancer cell lines. 
Noncancer cells tolerate ATR inhibition with only a transient growth arrest, as attributed to 
compensatory signaling mediated by ATM. M4344 showed better potency as a single-agent 
in a panel of cancer cells that harbored the Alternative Lengthening of Telomeres mechanism 
of telomere maintenance than those with a telomerase mechanism of telomere maintenance. 
As monotherapy, orally administered M4344 inhibited tumor growth in a mouse xenograft 
model of colorectal cancer with defective ATM and expression of oncogenes that drive high 
RS levels. In combination, M4344 was well tolerated and enhanced the antitumor effects of 
the DNA-damaging agents cisplatin, carboplatin, irinotecan, and gemcitabine in a dose-
dependent manner in mouse xenograft models. 
8.C.2.2.2 
Nonclinical Pharmacokinetics 
M4344 was observed to have a high intrinsic permeability with an apparent permeability 
coefficient of 19.2 × 10-6 cm/sec (A to B) and 32.1 × 10-6 cm/sec (B to A) in wild-type 
Madin-Darby Canine Kidney (WT-MDCK) cells. Significant directional efflux of M4344 
was observed (efflux ratio of 26.7) at a concentration of 1 µM in the multi-drug resistant 
protein-1 (MDR-1) transfected MDCK cell line. 
Following oral administration, M4344 was rapidly absorbed and exposure increased with 
dose in rats and dogs. The oral bioavailability in rats, dogs, and cynomolgus monkeys was 
49.5%, 67% and 34%, respectively. M4344 was well distributed into tissues after oral 
administration with a volume of distribution of 0.99 L/kg to 1.84 L/kg in mouse, rat, dog, and 
monkey. 
In vitro protein binding of M4344 was assessed in mouse, rat, dog, and monkey plasma, and 
to human serum albumin and AAG over the range of 0.15 to 15 µM. A moderate/ high free 
fraction was observed in all species with indications for saturation of binding at the highest 
test item concentration of 15 µM, which is not caused by a strong affinity to AAG. In human 
plasma, M4344 has an average free fraction of 0.319. 
M4344 was rapidly taken up into cryopreserved hepatocytes in vitro. The low effect of 
inhibitors of the transporters OATP-1B1, OATP-1B3 and OCT-1 suggests these transporters 
do not contribute significantly to the hepatic uptake of M4344. 
The primary routes of metabolism for M4344 include CYP3A4 and aldehyde oxidase. All the 
metabolites detected in human hepatocyte incubations were detected in the in vivo samples 
from either rat or dog, except the metabolite M11, and latterly the probable aldehyde oxidase 
simple mono-oxidation product M26 (VRT-1363170) 
A low potential for DDI was predicted based on minimal inhibition or induction of CYP 
isozymes by M4344. UGT1A1-mediated metabolism of bilirubin in human microsomes was 


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inhibited by M4344 (IC50 = 8.36 µM) and its metabolite M26 (IC50 = 1.1 µM). In Caco-
2/TC7 cells, M4344 was found to inhibit P-gp with an IC50 of 39 µM and inhibit BCRP with 
an IC50 of 4.2 µM. 
8.C.2.2.3 
Toxicology 
GLP 28-day toxicology studies were conducted following twice a week (BIW) 
administration of M4344 of up to 30 mg/kg in rats and up to 4 mg/kg in dogs. The identified 
hematological toxicity included reductions in white blood cell and red blood cell mass; 
lymphoid depletion, decreased lymphocytes/extramedullary hematopoiesis in the spleen; 
extramedullary hematopoiesis in the liver. Testicular toxicity was observed in both species. 
In addition, gastrointestinal toxicity was reported in dogs. These toxicities are considered 
reversible. A severely toxic dose to 10% of the population (STD10) in rats was not 
determined; the highest non-severely toxic dose (HNSTD) in dogs was 2 mg/kg BIW. 
M4344 did not affect cardiovascular endpoints in anaesthetized guinea pigs or in conscious 
dogs at tolerated doses in dedicated cardiovascular studies. M4344 was not mutagenic in a 
GLP 5-strain bacterial reverse mutation study. An initial photosafety assessment indicated 
that M4344 absorbs in the ultraviolet-visible range of the electromagnetic radiation spectrum 
and additional assessments of photosafety are planned for the appropriate phase of clinical 
development. 
8.C.2.3 
Clinical Experience 
To date, the clinical experience with M4344 is derived from ongoing Study MS201922-0001 
(Study 0001), an open-label, first-in-human (FIH) study comprising 3 active Parts (Parts A, 
A2, and B1). Part A is a dose-escalation study in patients with advanced solid tumors to 
investigate the safety, tolerability, and PK, as well as establish the MTD and/or RP2D of 
single-agent M4344 administered BIW and in addition, as QD or BID dosing in Part A2. Part 
B1 is a dose-escalation study in patients with advanced solid tumors to investigate the safety, 
tolerability, and PK, as well as establish the MTD and/or RP2D of M4344 administered in 
combination with carboplatin. 
As of 25 May 2018, 40 patients in Part A have received M4344 at doses ranging from 10 to 
1,200 mg BIW and 13 patients in Part B1 have received M4344 at doses between 350 mg and 
500 mg on Day 2 and Day 9 of a 21-day cycle in combination with carboplatin, administered 
on Day 1. 
8.C.2.3.1 
Clinical Pharmacology 
Preliminary human PK of M4344 in patients are available for Parts A and B1 from 
Study 0001. The PK of M4344 was characterized by a moderately fast absorption (maximum 
concentration [tmax] between 1 and 4 hours) followed by a rapid biphasic decline in most 
patients (t1/2of approximately 4 hours). Exposure estimates increased in a roughly dose-
proportional manner with increasing dose and with no evidence of study drug accumulation 
after BIW dosing. The variability in Cmax and AUC was high and similar on Days 1 and 8 for 
Part A. The apparent plasma clearance of the drug after oral administration (CL/F) and 
apparent volume of distribution during terminal phase after oral administration (Vz/F) were 


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large, ~400 L/hour (approximately 5-times hepatic blood flow) and ~30 L/Kg respectively, 
suggesting low bioavailability. 
The PK of M4344 in Part B1, in combination with carboplatin, were consistent with those 
observed in Part A. 
In all studies, M4344 was administered on an empty stomach, and the effect of food on the 
absorption of M4344 is currently unknown. 
As rucaparib is a weak clinical inhibitor of CYP3A using oral midazolam as a substrate, and 
both CYP3A4 and aldehyde oxidase are primarily involved in M4344 metabolism, a 
clinically significant effect of rucaparib on M4344 PK is not expected. 
8.C.2.3.2 
Efficacy 
Preliminary efficacy data (data cut-off date: 25 May 2018) are summarized for 40 patients in 
Study 0001 Part A (single-agent therapy) and 13 patients in Part B1 (M4344 and carboplatin 
AUC5). In Part A, 6 of 40 patients (15.0%) had stable disease (SD) as the best overall 
response; no patients had CR or PR. One patient reporting SD for > 2 years. In Part B1, 4 of 
13 patients (30.8%) had SD as the best overall response; no patients had CR or PR. 
8.C.2.3.3 
Safety 
Preliminary safety data (data cut-off date: 25 May 2018) are summarized for 40 patients in 
Study 0001 Part A who received single-agent therapy at doses ranging from 10 to 1,200 mg 
BIW and 13 patients in Study 0001 Part B1 who received M4344 at doses of 350 to 500 mg 
(Days 2 and 9 of a 21-day cycle) in combination with carboplatin at the dose AUC5 (Day 1). 
In Part A, all but 1 patient receiving M4344 BIW had AEs, and 36 of 40 patients (90.0%) had 
at least 1 AE (any Grade) considered by the investigator to be related to study drug treatment. 
The most common AE was nausea, occurring in 67.5% of patients. Other AEs occurring in at 
least 25% of patients were vomiting (19 patients, 47.5%), fatigue (17 patients, 42.5%), 
aspartate aminotransferase increased, and constipation (both 12 patients, 30.0%), blood 
bilirubin increased (11 patients, 27.5%), and alanine aminotransferase increased (10 patients, 
25.0%). Twenty-six patients (65.0%) had AEs of Grade 3 or higher. The most common AE 
of Grade 3 or higher was blood bilirubin increased (11 patients, 27.5%; in patients treated 
with ≥ 700 mg). Additionally, a total of 6 patients (15.0%) reported Grade 3 or higher AEs of 
ALT increased, and 7 patients (17.5%) Grade 3 or higher AEs of AST increased. One patient 
in Part A had an AE leading to death (death-unknown cause). The investigator noted that this 
death was related to cancer, not to M4344. 
In Part B1, all treated patients had AEs; all patients also reported AEs that were considered 
by the investigator to be related to M4344 and AEs that were considered by the investigator 
to be related to carboplatin. The most commonly reported AE was fatigue (10 patients 
[76.9%]). Twelve patients (92.3%) reported an AE of Grade 3 or higher; the most common 
was neutropenia (7 patients [53.8%]). 


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Treatment-emergent AEs that led to discontinuation of study drug in Study 0001 Part A 
occurred in 13 patients (32.5%), the most common TEAEs leading to discontinuation were 
blood bilirubin increased and nausea (both reported in 3 patients [7.5%]).  
Treatment-emergent AEs that led to discontinuation of study drug in Study 0001 Part B1 
occurred in 2 patients (15.4%) in the M4344 500 mg and carboplatin AUC5 group: both 
patients (15.4%) reported events of neutropenia; and events of thrombocytopenia and ALT 
increased were reported in 1 patient each (7.7%).  
Based on evaluation of safety data from Study 0001, elevations in hepatic transaminases 
(ALT and AST) have been established as a new important potential risk associated with the 
administration of M4344.  
For M4344, elevation of hepatic transaminases and bilirubin are defined as a treatment-
emergent AESIs. Elevations were seen in doses greater than 700 mg BIW. Details on AESIs 
for M4344 can be found in the current M4344 IB and reporting procedures are in 
Section 10.10. 
In Part A, DLTs confirmed in dose escalation meetings occurred in 3 of 40 patients in the 
safety set. One patient in the 1,050-mg group had DLTs of ALT and AST increased, blood 
bilirubin increased, and neutropenia. Two patients in the 1,200-mg group had a DLT of blood 
bilirubin increased. No DLTs occurred at M4344 doses from 10 to 700 mg BIW. 
In Part B1, DLTs confirmed in dose escalation meetings occurred in 4 of 13 patients in the 
safety set. All DLTs were reported in patients receiving M4344 500 mg and AUC5 
carboplatin. Three patients had a DLT of neutropenia; DLTs of febrile neutropenia, 
gastrointestinal inflammation, thrombocytopenia, and vomiting were reported in 1 patient 
each. 
8.C.2.3.3.1 
Adverse Drug Reactions for M4344 
Hyperbilirubenemia 
M4344 causes hyperbilirubinemia via dose-dependent inhibition of bilirubin glucuronidation 
by UGT1A1 that has not impaired hepatic function (other than bilirubin metabolism). Before 
this mechanism was known, increased blood bilirubin and hyperbilirubinemia were reported 
as DLTs in 3 patients. These 3 events were also reported as SAEs and resulted in study drug 
withdrawal. After the mechanism of hyperbilirubinemia was determined based on a review of 
clinical and nonclinical data and outside expert assessment, the definition of a DLT was 
revised in a 2016 protocol amendment to exclude increases in bilirubin that are assessed as 
arising from inhibition of bilirubin glucuronidation, as long as the bilirubin level remains 
below 15 mg/dL (257 μmol/L). After this revision, no DLTs were reported. Overall, DLTs 
occurred in 3 of 21 patients (14.3%) in the DLT evaluable set; these were the 3 patients 
experiencing significant hyperbilirubinemia prior to the revision of the DLT definition. This 
effect has been observed at doses ≥ 300 mg BIW M4344. The onset of increased blood 
bilirubin is within 1 day of administration of the drug and may be severe (ie, Grade ≥ 3), 
although elevation of bilirubin due to M4344 has not resulted in any adverse consequences. 
The incidence of increased blood bilirubin as an SAE is also dose dependent and has been 


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reported at doses ≥ 700 mg BIW. Both patients in the 1,200 mg BIW dose group, the highest 
M4344 dose administered in Study 001 Part A, had DLTs of blood bilirubin increased or 
hyperbilirubinemia. These were also reported as SAEs. 
Nausea and Vomiting 
In Study 001 Part A, nausea occurred in 67.7% of patients and vomiting in 47.5%. These 
events have usually been non-serious, Grade 1 or Grade 2. Many of the events of nausea and 
vomiting occurred on the same day as M4344 administration. 
 Rationale for Rucaparib and M4344 Combination 
PARP inhibitors capitalize upon synthetic lethality by impairing the repair of single-stranded 
DNA breaks, leading to DNA double-strand breaks, which cannot be repaired efficiently in 
BRCA1/2 mutant cancers. It has been postulated that PARP inhibitor therapy could be 
optimized by interfering with cell-cycle checkpoint signaling, thereby further modulating the 
DNA repair activity. ATR and its downstream kinase CHK1 are activated by DNA 
replication stress and DNA damage, thereby arresting cell-cycle progression allowing time 
for appropriate damage repair and completion of replication. ATR/CHK1 blockade prevents 
DNA damage-induced cell-cycle arrest, resulting in inappropriate entry into mitosis, 
chromosome aberrations, unequal partitioning of the genome, and ultimately apoptosis. 
To this end, it has been postulated that a combination of rucaparib with M4344 could 
potentially bring about synergistic antineoplastic effects. ATR is recruited to DNA damage 
lesions during the S and G2 phases of the cell cycle, where it coordinates a series of 
responses, including checkpoint activation and DNA repair by homologous recombination. 
PARP inhibition results in double-strand DNA breaks in S-phase and requires ATR activity 
for efficient DNA repair. Nonclinical data indicate that ATR inhibition increases sensitivity 
to PARP inhibition10 and that defects in ATR signaling can potentially result in synthetic 
lethality with PARP inhibitors.11 Inhibition of ATR may be a mechanism to overcome 
primary and acquired resistance to PARP inhibition. 
8.C.3.1 
Dose and Duration Rationale 
The starting doses for the combination of M4344 and rucaparib are selected to provide a 
safety margin relative to previous clinical experience of each agent as monotherapy and 
further supported based on preclinical xenograft studies. 
A dose-escalation study is currently ongoing to evaluate the safety, tolerability, and PK, as 
well as establish the MTD and RP2D of M4344 when administered as a single agent in 
patients with advanced solid tumors (Study 0001). Starting doses were explored in Parts A 
and A2. A 100-mg dose administered BID (200 mg daily) was selected as the starting dose 
for Part A2. This starting dose in Part A2 was based on the available clinical experience in 
36 patients treated with up to the 1,200 mg BIW dosing schedule in Part A. In Part A, DLTs 
confirmed in dose escalation meetings occurred in 3 of 40 participants in the safety set 
(1 patient who received 1,050 mg BIW M4344 and 2 patients who received 1,200 mg BIW 
M4344). No DLTs were observed at M4344 doses of 10 to 700 mg BIW. The 1,200 mg BIW 


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schedule results in a total weekly dose of 2,400 mg. A 100-mg dose administered BID results 
in a total weekly dose of 1,400 mg and is therefore expected to be a tolerable starting dose. 
The RP2D is still being determined.  
Expected gastrointestinal-associated toxicities of nausea, vomiting, and toxicities associated 
with myelosuppression, such as neutropenia, are potentially overlapping with a rucaparib and 
M4344 treatment. Additionally, M4344 exposure is associated with dose-dependent 
hyperbilirubinemia; as well, elevations in hepatic transaminases (ALT and AST) have been 
established as a new important potential risk associated with the administration of M4344, 
and rucaparib is associated with transaminase elevation. Given these potentially overlapping 
toxicities, the initial dose cohort to be evaluated in the Phase 1b will consist of a dose of 
rucaparib at 50% of the marketed monotherapy starting dose (ie, 300 mg BID) and a dose of 
M4344 (ie, 50 mg QD) that is 25% of the starting dose in the current monotherapy M4344 
Phase 1, part A2 study (100 mg BID). Pharmacokinetic/pharmacodynamic modeling results 
further suggest that the selected starting M4344 dose of 50 mg QD would result in 
steady-state plasma exposure of unbound M4344 that is 50% lower than the minimum 
biologically active exposure in a mouse xenograft model. Incremental increases are planned 
as described in Section 8.C.4.2.1. Doses of rucaparib and/or M4344 less than aforementioned 
dose levels or including less frequent dosing or administered on a modified dosing schedule 
may be evaluated based on unacceptable toxicities observed the initial dose cohort. 
8.C.3.2 
Expansion Cohorts Rationale 
After Phase 1b and determination of the RP2D, the study will evaluate 2 cohorts: patients 
with ovarian cancer who have progressed on prior PARP inhibitor treatment and patients 
with solid tumors harboring a deleterious ATM alteration or ATM loss (eg, 0% protein 
staining based on an IHC assay) who are more susceptible to ATR inhibition. 
PARP inhibitors have been well studied in patients with ovarian cancer; therefore, ovarian 
tumors were selected for inclusion as a Phase 2 expansion cohort. A nonclinical study of 
olaparib in combination with AZD6738, an ATR inhibitor, was evaluated in a BRCAmut 
patient-derived xenograft (PDX) model of ovarian cancer.99 Targeting the ATR/ CHK1 Axis 
with PARP inhibition results in tumor regression in BRCAmut ovarian cancer models. The 
authors found that the PARP inhibitor treatment resulted in early activation of ATR/ CHK1 
and that the combination PARP inhibitor with the ATR inhibitor was synergistic in 
suppressing BRCAmut high-grade serous ovarian cancer (HGSOC). In the PDX model, PARP 
inhibitor and ATR inhibitor combination led to significantly more tumor regression, with 
57% of mice having a complete remission compared to no complete remissions in the single-
agent PARP inhibitor treatment, and only 14% in the PARP inhibitor and CHK1 inhibitor 
combination, the other combination being studied. The combination of a PARP inhibitor and 
ATR inhibitor may have activity in tumors that are PARP inhibitor resistant due to 
homologous recombination restoration by targeting earlier events in HRR, for example 
ATM/ATR phosphorylation at sites of DNA damage. 
Additionally, there is scientific rationale that a combination of an ATR inhibitor and 
rucaparib may be effective in tumors harboring a deleterious ATM alteration or ATM loss. 
The ATR is the primary mediator of an important DNA damage surveillance and repair 


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pathway that responds to RS.100 Replication stress arises when the cell's DNA replication 
machinery attempts to copy through an unresolved damage lesion. Such events are common 
after cells are treated with DNA‑damaging agents. Left unresolved, RS can lead to DSB and 
cell death. The RS pathway is closely associated with a DSB repair pathway mediated by 
ATM.83 Inhibition of ATR in noncancer cells has been shown to lead to activation of a 
compensatory ATM-mediated response that protects cells from the lethal consequences of 
unrepaired RS.84 In contrast, many cancer cells depend on ATR for survival from DNA 
damage as a result of defects in the ATM-signaling pathway and/or as a result of high 
background levels of RS that can arise from a number of mechanisms, including expression 
of certain oncogenes.85-88 Such defects in ATM signaling can cause a dependence on ATR 
for survival from RS caused by treatment with DNA‑damaging agents.84,89-93 Accordingly, 
while noncancer cells have been shown to tolerate combinations of ATR inhibitors and 
DNA‑damaging drugs, it is expected that an ATR inhibitor will sensitize many cancer cells 
to various DNA‑damaging agents.84 High levels of RS are evident in some cancer cells even 
in the absence of DNA‑damaging agents. This can result from expression of oncogenes that 
drive dysregulated replication, a hypoxic environment, or from defects in other DNA repair 
pathways. This high RS in cancer cells can drive a reliance on ATR for survival and thus, 
ATR inhibitors may have benefit as single agents.94-98 
 Treatment Arm C Study Design 
Treatment Arm C of this study will investigate the safety, tolerability, PK, and preliminary 
efficacy of the PARP inhibitor, rucaparib, in combination with the ATR inhibitor, M4344.  
As described in Section 3.1, the treatment arm will consist of 2 phases: Phase 1b is a 
dose-escalation phase primarily to determine the MTD and RP2D of the combination of 
rucaparib and M4344; and Phase 2 investigates the RP2D for the combination of rucaparib 
and M4344 in patients with prespecified tumor types. 
For patients enrolled into Treatment Arm C (Phase 1b or Phase 2) of the study, patients will 
receive rucaparib BID and M4344 QD or BID continuously in 28-day cycles. 
8.C.4.1 
Treatment Arm C Screening and Enrollment 
All patients will undergo screening assessments, including disease status per RECIST v1.1, 
prior to enrollment, within the time frame specified by the Schedule of Assessments 
(Table 8.C-4).  
Treatment Arm C will enroll patients who have met all of the inclusion criteria and none of 
the exclusion criteria presented in Section 8.C.5.2 and Section 8.C.5.3, respectively. The 
criteria may be different depending upon which phase of Treatment Arm C the patient is 
enrolled; these specific criteria are indicated, as appropriate. 
Phase 1b will enroll adult patients with a locally advanced or metastatic solid tumor that has 
progressed on standard treatment. 
Phase 2 will enroll patients into 1 of 2 cohorts: 


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Cohort C1: 
Patients with ovarian cancer that have progressed on prior PARP inhibitor 
therapy 
Cohort C2: 
Patients with locally advanced or metastatic solid tumor with a deleterious 
ATM alteration or ATM loss (eg, 0% protein staining based on an IHC 
assay) 
Patients enrolled into Cohort C1 will have received prior monotherapy PARP inhibitor 
treatment as their most recent treatment and have confirmed PR or CR or stable disease for 
≥ 6 months on PARP inhibitor prior to disease progression. Maintenance PARP inhibitor 
treatment following chemotherapy or other treatment is considered an eligible 
PARP-inhibitor regimen. 
8.C.4.2 
Treatment Arm C: Treatment Phase 
For both Phase 1b and Phase 1 of Treatment Arm C, patients will visit the study site on 
Day 1 and Day 15 of Cycles 1 and 2, and on Day 1 of every cycle thereafter (see 
Table 8.C-4).  
Patients will be assessed for disease status per RECIST v1.1 every 8 calendar weeks 
(±1 week) for the first 18 months following initiation of combination study treatment 
(Cycle 1 Day 1), then every 16 weeks (±1 week) thereafter until radiological disease 
progression as assessed by the investigator, death, loss to follow-up, withdrawal from study, 
study termination, or initiation of subsequent anticancer treatments. Responses (CR or PR) 
must be confirmed with a scan no less than 4 weeks after initial response. 
8.C.4.2.1 
Phase 1b 
Phase 1b is based on a standard 3+3 design as described in Section 3.1.3.1. The first dose of 
combination study treatment (rucaparib and M4344) will be administered on Day 1 of 
Cycle 1. The first 28 days of study treatment (Cycle 1) is the DLT-evaluation period. During 
the DLT-evaluation period, patients will come into the study site for a visit on Day 1 and 
Day 15. 
The initial combination dose consists of oral rucaparib 300 mg BID and oral M4344 50 mg 
QD. The dose of rucaparib will be escalated in 100 mg BID increments up to a maximum of 
600 mg BID. The dose of M4344 will be first increased to 50 mg BID, then increased in 
increments of 50 mg or 100 mg QD or BID to a maximum dose of 500 mg BID. Once the 
initial dose has been evaluated and deemed safe and tolerable, parallel cohorts, where the 
dose of 1 investigational agent remains the same as in the prior cohort while the dose of the 
other agent is escalated, may be evaluated going forward. For example, a cohort receiving 
400 mg BID rucaparib in combination with 50 mg QD M4344 may be evaluated in parallel 
with a separate cohort receiving 300 mg BID rucaparib in combination with 50 mg BID 
M4344. In the event that QD or BID dosing of M4344 in combination with BID dosing of 
rucaparib is not tolerable, alternative dosing schedules may be explored. For example, 
M4344 may be administered less frequently (eg, evaluation of QD dosing only or 
administration 2 or 3 times weekly) or a treatment interruption may be introduced (eg, 
M4344 administered on Days 1 to 14 only). All decisions regarding evaluation of an 


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alternative dosing schedule will be made between the sponsor and investigators based on 
available safety, and PK data. 
Prior to initiating treatment at each new combined dose level or prior to expanding an 
existing dose level, a safety teleconference will be held to review patient data, including but 
not limited to demographics, PK results (if available), study drug combination dosing, 
concomitant medications, hematology and chemistry, and AEs, and then confer and 
document agreement that dose escalation and/or expanding an existing dose level is/are 
considered appropriately safe. Safety teleconferences will include study investigators, the 
sponsor’s medical monitor, and may include other representatives or designees of the sponsor 
and the study sites. 
Dose modifications will be made based on clinical judgement and the dose modification 
guidance provided in Section 8.C.6.4. 
8.C.4.2.1.1 
Dose-limiting Toxicity Criteria 
A DLT considered for dose escalation in Phase 1b is defined as any of the following 
occurring within the first 28 days of initiating combination treatment (Cycle 1) that is 
assessed by the investigator as possibly related to rucaparib and/or M4344 (refer to 
Section 10.7.4 for consideration of causal relationship). Where applicable, event will be 
classified, according to NCI CTCAE v5.0. 
• Grade 3 or greater febrile neutropenia (ie, fever > 38.3°C with ANC < 1.0 × 109/L) of any 
duration; 
• Grade 3 or 4 neutropenia lasting more than 7 days despite GCSF administration; 
• Grade 3 thrombocytopenia (platelets < 50 × 109/L) with significant bleeding or Grade 4 
thrombocytopenia (platelets < 25 × 109/L) ≥ 5 days duration; 
• Grade 4 anemia (ie, life-threatening consequences; urgent intervention indicated) or any 
anemia (regardless of grade or severity) requiring a blood transfusion; 
• Any nonhematological AE ≥ Grade 3, with the exception of: 
- 
Nausea, vomiting, and diarrhea well controlled by systemic medication and with 
duration ≤ 48 hrs; 
- 
Fatigue; 
- 
Grade 3 ALT or AST not accompanied by a concomitant increase in total bilirubin 
above the ULN. Note: any Grade 4 ALT/AST is a DLT; 
- 
Increases in indirect bilirubin assessed as arising from inhibition of bilirubin 
glucuronidation by UGT1A1, provided bilirubin remains below 15 mg/dL 
(257 µmol/L).  
 
If a patient is not evaluable for a DLT, then an additional patient may be enrolled. For the 
definition of evaluability, please refer to Section 9.2.  


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8.C.4.2.1.2 
 
RP2D Selection and Expansion 
As described in Section 3.1.3.1.2, once the RP2D of the combination has been provisionally 
established, up to 10 additional patients may be enrolled and treated in Phase 1b, in order to 
further characterize safety, tolerability, and PK and confirm that this is the optimal dose 
combination to evaluate in the Phase 2 portion. 
8.C.4.2.1.3 
Phase 1b – Cycle 2 and Beyond 
Following the DLT-evaluation period, patients will come into the study site for a visit on 
Day 1 and Day 15 of Cycle 2, and on Day 1 of every cycle thereafter. Patients will be 
monitored for safety, PK, and efficacy as outlined in the Schedule of Assessments 
(Table 8.C-4) and PK Assessments (Table 8.C-5). 
After the 28-day DLT-evaluation period, recommendations for rucaparib and M4344 dose 
modification for the management of specific AEs are provided in Section 8.C.6.4. 
Patients tolerating the investigational treatment(s) at the assigned dose combination for at 
least 4 cycles may be permitted to escalate to the next highest combination dose regimen as 
long as the new dose regimen is lower than that being currently evaluated for safety and 
tolerability and/or the dose level is the same or lower than that determined to be the RP2D. 
All individual patient dose-escalation steps must be approved by the sponsor’s medical 
monitor. 
Patients will be treated until disease progression, unacceptable toxicity, patient or 
investigator request to discontinue, death, initiation of any other anticancer therapy, positive 
pregnancy test, or termination of the study (Section 3.2). If a patient receiving study drug has 
met criteria for radiologic disease progression by RECIST v1.1 criteria but continues to 
derive clinical benefit per the investigator, continuation of treatment may be permitted after 
discussion with the medical monitor (Section 5.9). 
8.C.4.2.2 
Phase 2 Cohorts 
Upon determination of the RP2D from Phase 1b, Phase 2 will be initiated. In Phase 2, the 
selected RP2D from Phase 1b will be evaluated using Simon 2-stage designs in separate and 
parallel cohorts (see Section 8.C.9.1). Patients meeting all eligibility criteria will be enrolled 
into 1 of 2 cohorts as follows: 
Cohort C1: 
Patients with ovarian cancer that has progressed on prior PARP inhibitor 
therapy 
Cohort C2: 
Patients with locally advanced or metastatic solid tumor associated with a 
deleterious ATM alteration or ATM loss (eg, 0% protein staining based on 
an IHC assay) 
 
The Phase 2 cohorts were chosen due to the potential susceptibility to the combination of 
rucaparib and M4344 (Section 8.C.3.2).  


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The RP2D of the combination of rucaparib and M4344 may be further adjusted, and/or 
alternative dosing schedules assessed during Phase 2 based on emerging safety, PK, and 
efficacy data.  
Patients will be monitored for safety, PK, and efficacy as outlined in the Schedule of 
Assessments (Table 8.C-4) and PK Assessments (Table 8.C-5). 
Dose modification guidelines in Section 8.C.6.4 should be followed throughout the Phase 2.  
Patients will be treated until disease progression, unacceptable toxicity, patient or 
investigator request to discontinue, death, initiation of any other cancer therapy, positive 
pregnancy test, or termination of the study (Section 3.2). If a patient receiving study drug has 
met criteria for radiologic disease progression by RECIST v1.1 criteria but continues to 
derive clinical benefit per the investigator, continuation of treatment may be permitted after 
discussion with the medical monitor (Section 5.9). 
8.C.4.3 
End of Treatment Arm C and Safety Follow-up 
Upon treatment discontinuation, regardless of reason (with the exception of withdrawal of 
consent or death), patients will have an End of Treatment Visit, and assessments are specified 
for each treatment arm in the Schedule of Assessments within Table 8.C-4. All patients will 
be followed for at least 28 days after the last dose of study drug. Safety follow-up 
assessments are specified for Treatment Arm C in the Schedule of Assessments. 
 Study Population Selection for Arm C 
8.C.5.1 
Treatment Arm C: Number of Patients and Sites 
In Phase 1b, it is estimated that up to 55 patients will be enrolled, dependent upon the 
number of dose cohorts enrolled.  
In Phase 2, up to 80 patients will be enrolled into the following cohorts:  
Cohort C1: 
Up to 40 patients with ovarian cancer that has progressed on prior PARP 
inhibitor therapy 
Cohort C2: 
Up to 40 patients with locally advanced or metastatic solid tumor 
associated with a deleterious ATM alteration or ATM loss based on IHC. 
(Note: no more than 10 patients with ATM loss will be enrolled). 
Patients will enroll into either Phase 1b or Phase 2, but a patient cannot enroll into both 
phases of the same treatment arm. For Phase 2, patients will enroll simultaneously across 
both cohorts based on separate Simon 2-stage designs for each cohort. Enrollment into 
Phase 2 for each cohort will continue until the required number of patients for each stage is 
reached (Section 8.C.9.1). 
The enrollment of the 2 phases in Treatment Arm C of the study is approximately 
135 patients. It is planned that 3 to 6 sites in the US are expected to participate in Phase 1b of 


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the study; approximately 25 sites globally may be activated to participate in the Phase 2 
portion of the study. 
8.C.5.2 
Treatment Arm C: Inclusion Criteria 
All patients participating in Treatment Arm C must meet all of the following inclusion 
criteria: 
1. Have signed an IRB/IEC-approved ICF prior to any study-specific evaluation; 
2. Be ≥ 18 years of age at the time the ICF is signed; 
3. Have an ECOG performance status of 0 to 1; 
4. Have life expectancy of at least 3 months per investigator discretion; 
5. Have adequate organ function confirmed by the following laboratory values obtained 
within 14 days of the first dose of study drug: 
a. Bone Marrow Function 
i. 
ANC ≥ 1.5 × 109/L; 
ii. 
Platelets > 100 × 109/L;  
iii. 
Hemoglobin ≥ 9 g/dL  
Note: All hematology values must be achieved without the need for transfusion or 
growth factors ≤ 14 days prior to the planned start of study treatment (C1D1); 
b. Hepatic Function 
i. 
AST and ALT ≤ 3 × institutional ULN; if liver metastases, then ≤ 5 × the 
institutional ULN; 
ii. 
Total bilirubin ≤ 1.5 × institutional ULN; 
iii. 
Albumin ≥ 30 g/L (3.0 g/dL). 
c. Renal Function  
i. 
Creatinine ≤ 1.5 × institutional ULN OR eGFR ≥ 45 mL/min using the 
Cockcroft-Gault formula (Appendix 1); 
ii. 
Less than or equal to 1+ proteinuria. Patients with ≥ 1+ proteinuria on dipstick 
must perform have a 24-hour urine collection demonstrating ≤ 1.0 g over 
24 hours; 
6. Have sufficient archival or more recently obtained FFPE tumor tissue available for 
genomic analysis (refer to Section 7.5.1); 
7. Phase 1b: Have a histologically or cytologically confirmed solid tumor that is locally 
advanced or metastatic and has progressed on standard treatment; 
8. Phase 1b: Have disease that is evaluable per RECIST v1.1; 
9. Phase 2: Criteria specific to Phase 2 cohorts: 
a. Have locally advanced or metastatic disease that has progressed on standard 
treatment; 
b. Have measurable disease as defined by RECIST v1.1; 
AND 


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c. For Cohort C1: 
i. 
Have EOC, FTC, or PPC that has progressed following monotherapy PARP 
inhibitor treatment (rucaparib, olaparib, niraparib, or talazoparib); 
ii. 
PARP inhibitor must have been the last treatment received; maintenance PARP 
inhibitor treatment following chemotherapy or other treatment is also considered 
an eligible PARP inhibitor regimen; 
iii. 
Must have had confirmed PR or CR or SD ≥ 6 months on PARP inhibitor 
treatment prior to disease progression; 
iv. 
Must have disease that can be biopsied prior to receiving study drug treatment; 
d. For Cohort C2:  
i. 
Must have been previously tested and identified to have a deleterious ATM 
alteration from tissue or plasma ctDNA results, per local CLIA-certified 
laboratory. Deleterious ATM alterations include protein truncating mutations, 
large protein-truncating rearrangements, splice site mutations, and homozygous 
deletions. Missense mutations would only be acceptable if the variant is classified 
as “pathogenic” or “likely pathogenic”, OR 
ii. 
Must have ATM loss (eg, 0% protein staining) based on an IHC assay performed 
in a local CLIA-certified laboratory. 
 
8.C.5.3 
Treatment Arm C Exclusion Criteria 
Patients who meet any of the following criteria will be excluded from Treatment Arm C: 
1. Unable to swallow oral study drug; 
2. Have active second malignancy, ie, patient known to have potentially fatal cancer present 
for which he/she may be (but not necessarily) currently receiving treatment;  
Note: Patients with a history of malignancy that has been completely treated, with no 
evidence of active cancer for 3 years prior to enrollment, or patients with surgically-cured 
low-risk tumors, such as early-stage cervical or endometrial cancer are allowed to enroll. 
Patients receiving anticancer hormonal therapy in the maintenance setting are allowed to 
enroll. 
3. For Phase 2, Cohort C2:  Have had prior treatment with any PARP inhibitor; 
4. Have symptomatic and/or untreated CNS metastases. Patients with asymptomatic, 
previously-treated CNS metastases are eligible provided they have been clinically stable 
(not requiring steroids for at least 8 weeks prior to first dose of study drug) and have had 
appropriate scans at the screening assessment;  
5. Have known HIV or AIDS-related illness, or history of chronic hepatitis B or C, with the 
exception of patients with sustained virologic response after completion of treatment for 
hepatitis C; 
6. Have received chemotherapy radiation, antibody therapy, or other immunotherapy, gene 
therapy, vaccine therapy, or experimental drugs ≤ 14 days prior to first dose of study 
drugs; 


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7. Have ongoing toxicity from prior cancer treatment ≥ Grade 2 by NCI CTCAE v5.0, 
except alopecia; additionally, ongoing Grade 2 peripheral neuropathy may be permitted 
with prior advanced approval from the sponsor;  
8. Has had a nonstudy-related minor surgical procedure ≤ 5 days, or major surgical 
procedure ≤ 21 days, prior to first scheduled dose of study drug. In all cases, the patient 
must be sufficiently recovered and stable before treatment administration; 
9. For female patients of childbearing potential and all male patients, the following are 
exclusion criteria, as applicable: 
a. Refusal to use highly effective method of contraception or to practice true abstinence 
during treatment and for 6 months after the last dose of rucaparib study treatment; 
b. Pregnant or breast feeding;  
c. Women of childbearing potential must not be considering getting pregnant during the 
study and for 6 months following the last dose of study drug; 
d. Male patients who refuse to use condoms during sex during and up to 6 months after 
study treatment. Male patients must not make semen donations during treatment and 
for 6 months following the last dose of rucaparib; 
10. Have any serious or unstable concomitant systemic disorder incompatible with the 
clinical study (eg, substance abuse, psychiatric disturbance, or uncontrolled intercurrent 
illness including active infection, arterial thrombosis, and symptomatic pulmonary 
embolism); 
11. Have a known history of MDS; 
12. Have any other condition that may increase the risk associated with study participation or 
may interfere with the interpretation of study results, and, in the opinion of the 
investigator, would make the patient inappropriate for entry into the study; 
13. Are receiving treatment with medications that are known to be strong inhibitors or 
inducers of CYP3A4 that cannot be discontinued at least 1 week before first dose of 
study drug and for the duration of the study; 
14. Cannot comply with restrictions for medications or food. Specifically, any subject who 
must continue on daily antacid therapy, such as, but not limited to, daily proton pump 
inhibitor (PPI) therapy or daily H2 blocker therapy; 
15. Patients of reproductive potential (male and female) must practice an effective method of 
contraception during treatment and for 6 months following the last dose of rucaparib. 
 
No waivers of these inclusion or exclusion criteria will be granted by the investigator and the 
sponsor or its designee. 
8.C.5.4 
Patients or Partners of Patients of Reproductive Potential 
Refer to Section 4.1. 
 Study Treatment(s): Arm C 
Refer to Section 5 for rucaparib treatment. 


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8.C.6.1 
Investigational Drug Product – M4344 
M4344 (formerly known as VX-803) is an oral formulation. M4344 tablets for oral 
administration will be supplied to the study sites by the sponsor. A brief description of 
M4344 is provided in Table 8.C-1 with details in the Pharmacy Manual. 
Table 8.C-1  Description of M4344 
Drug Name 
M4344 
INN 
M4344 
Formulation 
M4344 is formulated as immediate release 50 mg tablets for oral 
administration. Tablets are off-white to yellow and round. 
How Supplied 
50 mg tablets in bulk bottles, each containing 20 tablets. 
Storage Conditions 
Tablets should be stored ≤ 25°C with no freezing allowed. 
 
8.C.6.2 
M4344 Packaging and Labeling 
The sponsor will supply 50 mg M4344 tablets. Study drug labeling will be in compliance 
with applicable local and national regulations. Additional details regarding packaging, 
labeling, and dispensing for M4344 will be included in the Pharmacy Manual. 
8.C.6.3 
Preparation and Administration of M4344 
M4344, in combination with rucaparib, will be administered orally QD or BID on an empty 
stomach (abstain from food 2 hours before and 1 hour after dosing) at approximately the 
same time each day and at the same time as rucaparib. There are no strict requirements 
regarding the order in which rucaparib and M4344 should be ingested by the patient; 
however, on PK days, the 2 medications should be dosed as closely together as possible for 
convenient PK sampling. Administration conditions may be revised based on emerging data 
regarding food effect on PK of M4344 from other studies. 
8.C.6.4 
Dose Modification and Retreatment Criteria for Rucaparib and M4344 
Toxicities should be managed with supportive care and with dose modification for each of 
the study drugs according to the attribution of causality for the toxicity based on investigator 
judgement and consultation with the sponsor, as appropriate. A dose modification of 
rucaparib or M4344 is permitted, with the other dose remaining constant, if the causality is 
believed to be related to 1 study drug, but not the other. General management of specific AEs 
are described for rucaparib and M4344 in Table 8.C-2. Management of new or worsening 
pulmonary symptoms is described in Section 8.C.6.4.1. 
At the discretion of the investigator, the dose of rucaparib and/or M4344 may be held and/or 
reduced for Grade 2 toxicity that is attributed to either rucaparib or M4344 alone, or in 
combination, and not adequately controlled by concomitant medications and/or supportive 
care. 


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If any blood parameters remain clinically abnormal after 3 weeks of dose interruption, the 
patient should be referred for further evaluation, as clinically appropriate. For clinically 
significant hematology results, bone marrow analysis and blood cytogenetic analysis should 
be considered according to standard hematological practice. 
If a patient continues to experience the same toxicity despite multiple dose reduction steps to 
the lowest allowable dose, or if dosing with either study drug is interrupted for > 21 
consecutive days due to the toxicity, study treatment should be discontinued, unless 
otherwise agreed upon between the investigator and the sponsor. If either rucaparib or 
M4344 is interrupted for greater than 21 days, the patient may be discontinued from the study 
(Section 8.C.6.4.3). 


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Table 8.C-2 Dose Modification and Retreatment Criteria for Rucaparib and M4344 
Adverse Event including 
Laboratory Abnormalities 
Severity 
(CTCAE 
Grade) 
Rucaparib 
M4344 
Treatment 
Interruption 
Re-treatment 
Dose 
Modification 
Treatment 
Interruption 
Re-treatment 
Dose 
Modification 
Non-hematological Events 
Adverse event or laboratory 
abnormality 
1 or 2 
Nonea 
N/A 
Nonea 
Nonea 
N/A 
Nonea 
Adverse event or laboratory 
abnormalityb 
3 or 4 
Hold dose 
≤ Grade 2 
1st occurrence: 
Same dosea 
2nd occurrence of 
same AE: 
Reduce dosec 
3rd occurrence of 
same AE: 
Discontinue 
Hold dose 
≤ Grade 2 
1st occurrence: 
25% reductionc 
2nd occurrence 
of same AE: 
50% reductionc 
3rd occurrence 
of same AE: 
Discontinue  
ALT/AST elevation  
(in the absence of other signs 
of liver dysfunction) 
3 
Continuation of 
dosing permitted 
provided total 
bilirubin is 
< ULN and ALP 
is < 3 x ULN; 
monitor LFTs 
weekly; 
Hold if levels do 
not decline to 
≤ Grade 2 within 
2 weeks or if 
levels increase 
≤ Grade 2 
1st occurrence: 
Same dosea 
2nd occurrence of 
same AE: 
Reduce dosec 
3rd occurrence of 
same AE: 
Discontinue 
Continuation of 
dosing permitted 
provided total 
bilirubin is 
< ULN and ALP 
is < 3 x ULN; 
monitor LFTs 
weekly; 
Hold if levels do 
not decline to 
≤ Grade 2 within 
2 weeks or if 
levels increase. 
If not recovered 
within 3 weeks: 
discontinue 
≤ Grade 2 
1st occurrence: 
25% reductionc 
2nd occurrence: 
50% reductionc 
3rd occurrence: 
Discontinue  


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Table 8.C-2 Dose Modification and Retreatment Criteria for Rucaparib and M4344 
Adverse Event including 
Laboratory Abnormalities 
Severity 
(CTCAE 
Grade) 
Rucaparib 
M4344 
Treatment 
Interruption 
Re-treatment 
Dose 
Modification 
Treatment 
Interruption 
Re-treatment 
Dose 
Modification 
ALT/AST elevation 
4 
Hold; 
monitor LFTs 
weekly. 
≤ Grade 2 
Reduce dosec 
Monitor LFTs 
weekly for 
3 weeks after 
restart of study 
drug;  
If > 2nd 
occurrence: 
Discontinue 
Hold; 
monitor LFTs 
weekly. 
≤ Grade 2 
1st and 2nd 
occurrence: 
50% reductionc 
3rd occurrence: 
Discontinue 
ALT or AST elevations 
(> 3 × ULN) AND 
total bilirubin elevation 
(> 2 × ULN) - suspected 
DILI [Section 10.9]23,24 
NA 
Holdd; 
monitor LFTs 
weekly; 
≤ Grade 1 (or 
baseline) 
Subject to 
investigation: 
reduce dosec 
If DILI is 
confirmed, 
treatment should 
be permanently 
discontinued 
Holdd; 
monitor LFTs 
weekly; 
≤ Grade 1 (or 
baseline) 
Subject to 
investigation: 
reduce dosec 
If DILI is 
confirmed, 
treatment should 
be permanently 
discontinued  
Hematological Events 
Adverse event or laboratory 
abnormality 
1 or 2 
None 
N/A 
N/A 
None 
N/A 
N/A 
Adverse event (excluding 
exceptions below) 
3 or 4 
Hold dose 
≤ Grade 2 
1st occurrence: 
Same dose 
2nd occurrence of 
same AE: 
Reduce doseb 
3rd occurrence of 
same AE: 
Discontinue 
Hold dose 
≤ Grade 2 
1st occurrence: 
25% reductionc 
2nd occurrence 
of same AE: 
50% reductionc 
3rd occurrence: 
Discontinue  


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Table 8.C-2 Dose Modification and Retreatment Criteria for Rucaparib and M4344 
Adverse Event including 
Laboratory Abnormalities 
Severity 
(CTCAE 
Grade) 
Rucaparib 
M4344 
Treatment 
Interruption 
Re-treatment 
Dose 
Modification 
Treatment 
Interruption 
Re-treatment 
Dose 
Modification 
Anemia 
≥ 3 
Hold dosee 
≤ Grade 2 
Same or reduced 
dosea, c 
Hold dosee. 
≤ Grade 2 
Same or reduced 
dosea, c 
Instructions Specific to M4344 
Neutropenia  
Grade ≥3 
Instruction specific to M4344 
Hold dose 
Resume upon 
recovery to ≤ 
Grade 1 within 
3 weeks. growth 
factors should be 
used as clinically 
indicated.  
Resume at same 
dose if recovered 
within 7 daysa 
Grade 4 Neutropenia > 7 
days or febrile neutropenia 
of any duration 
(fever > 38.3°C with ANC < 
1.0 × 109/L) 
Grade 4 
Instruction specific to M4344 
Hold dose 
Resume upon 
recovery to ≤ 
Grade 1 within 
3 weeks. growth 
factors should be 
used as clinically 
indicated 
1st occurrence: 
25% reductionc; 
add growth 
factors 
2nd occurrence: 
50% reductionc 
3rd occurrence: 
Discontinue 
Hyperbilirubinemia 
Grade 3 
Instruction specific to M4344 
Hold dose 
≤ Grade 2 with 
dose held for 
≤ 14 days 
1st occurrence: 
25% reductionc 
2nd occurrence: 
50% reductionc 
3rd occurrence: 
Discontinue  


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Table 8.C-2 Dose Modification and Retreatment Criteria for Rucaparib and M4344 
Adverse Event including 
Laboratory Abnormalities 
Severity 
(CTCAE 
Grade) 
Rucaparib 
M4344 
Treatment 
Interruption 
Re-treatment 
Dose 
Modification 
Treatment 
Interruption 
Re-treatment 
Dose 
Modification 
Hyperbilirubinemia 
Grade 4 
Hold 
≤ Grade 2 
Reduce dosec; 
monitor LFTs 
weekly for 
3 weeks  
Hold 
≤ Grade 2 
1st or 2nd 
occurrence: 
50% reductionc 
3rd occurrence: 
Discontinue 
Abbreviations: AE = adverse event; ALT = alanine aminotransferase; AML = acute myeloid leukemia; ANC = absolute neutrophil count; AST = aspartate 
aminotransferase; BID = twice a day; CTCAE = Common Terminology Criteria for Adverse Events; LFTs = liver function tests; MDS = myelodysplastic 
syndrome; N/A = not applicable; QD = once a day; ULN = upper limit of normal. 
a 
Dosing of either study drug may be resumed at either the same dose or a lower dose, at the discretion of the investigator.  
b 
Exceptions include Grade 3 or 4 nausea, vomiting, or diarrhea adequately controlled with systemic antiemetic/antidiarrheal medication administered in 
standard doses according to institutional guidelines. 
c 
For dose reductions see Table 8.C-3. 
d 
Evaluate patient for the presence of confounding factors including malignant disease in the liver, co-administration of other suspect drugs, cholestasis, and 
viral or autoimmune hepatitis that could have caused the laboratory abnormalities. Other laboratory investigations of liver function such as INR should be 
implemented as indicated. If no alternative cause is identified, study drug must be permanently discontinued. Patients should be followed until all 
abnormalities have returned to normal, returned to baseline levels, or an alternative cause is found to explain the combination of the increased 
transaminases and total bilirubin. 
e 
If anemia CTCAE Grade ≥3 persists for > 14 consecutive days, or a dependence upon blood transfusions occurs, then weekly complete blood counts 
should be performed until resolution of the event. If after 42 days of interruption and anemia has not improved to CTCAE Grade ≤ 1, the patient should be 
referred to hematologist and analysis of the bone marrow with cytogenetic studies and recommended according to standard practice. Bone marrow analysis 
should include a bone marrow aspirate (for cellular morphology, cytogenetic analysis, and flow cytometry) and a core biopsy (for bone marrow 
cellularity). 


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8.C.6.4.1 
Management of New or Worsening Pulmonary Symptoms 
If new or worsening unexplained pulmonary symptoms suggestive of pneumonitis 
(including, but not limited to, dyspnea) occur, or a deterioration of pulmonary function is 
observed, and/or radiologic abnormality is detected in the lungs, and this occurs in the 
absence of any clear diagnosis, a diagnostic workup (including high resolution computed 
tomography [CT] scan) in consultation with a pulmonologist should be performed in order to 
rule out pneumonitis. During this time, treatment with rucaparib may be interrupted or 
continued per investigator discretion. M4344 treatment may also be interrupted or continued 
per investigator discretion. The contribution of M4344 should be assessed independently. 
Following investigation, if pneumonitis is not confirmed, treatment may be 
resumed/continued as deemed appropriate by the investigator and in accordance with the 
study protocol directions for management of AEs. All confirmed events of pneumonitis 
should be treated as appropriate per medical judgement and institutional guidelines. If the 
event resolves and retreatment is being considered, please consult the study Medical Monitor. 
Retreatment may be resumed at the current or a reduced dose, if appropriate.  
Refer to Section 10.7 and Section 10.8 of the protocol for additional information regarding 
classification and reporting of pneumonitis (and similar events, ie, interstitial lung disease, 
pulmonary fibrosis, acute interstitial pneumonitis, alveolitis necrotizing, alveolitis, 
hypersensitivity pneumonitis, and organizing pneumonia) as an AESI. 
8.C.6.4.2 
Rucaparib and/or M4344 Dose Reduction 
Potential dose reduction steps for rucaparib and M4344 based on different current doses are 
shown in Table 8.C-3. Rucaparib and M4344 dose reductions will occur in step-wise 
sequence. In the event that the initial dose level exceeds the MTD, other dosing schedules 
may be explored. 
Table 8.C-3 Rucaparib and M4344 Dose Reductions 
Rucaparib 
M4344 
Current Dosage 
Dose Reductiona 
Current Dosage 
Dose Reductiona 
25% 
50% 
600 mg BID 
500 mg BID 
500 mg BID 
750 mg daily 
(350 mg AM, 
400 mg PM) 
250 mg BID 
500 mg BID 
400 mg BID 
400 mg BID 
300 mg BID 
200 mg BID 
400 mg BID 
300 mg BID 
300 mg BID 
450 mg daily 
(200 mg AM, 
250 mg PM) 
150 mg BID 
300 mg BID 
200 mg BIDb 
200 mg BID 
150 mg BID 
100 mg BID 
- 
- 
100 mg BID 
150 mg daily 
(50 mg AM, 
100 mg PM) 
50 mg BID 


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Table 8.C-3 Rucaparib and M4344 Dose Reductions 
Rucaparib 
M4344 
Current Dosage 
Dose Reductiona 
Current Dosage 
Dose Reductiona 
25% 
50% 
- 
- 
50 mg BID  
None permitted 
50 mg QD 
- 
- 
50 mg QD 
None permitted 
Abbreviations: AM = morning (dose); BID = twice a day; PM = evening (dose); QD = once a day. 
a 
No more than 2 dose reductions for the same AE are allowed for either study drug, after which treatment 
with both study drugs will be discontinued. 
b 
Consult with sponsor’s medical monitor before reducing the dose of rucaparib to this level. 
 
8.C.6.4.3 
Rucaparib and/or M4344 Discontinuation 
Rucaparib and M4344 should be permanently discontinued for any of the following: 
• If a patient continues to experience toxicity despite dose reduction steps to the lowest 
permissible dose for either study drug (see Table 8.C-3) or if dosing with either study 
drug is interrupted for > 21 consecutive days due to toxicity, treatment with both study 
drugs should be discontinued, with the following exceptions: 
- 
Treatment interruption > 21 days may be allowed if approved by the sponsor. Prior to 
re-initiating treatment in a patient with a treatment interruption lasting > 21 days, the 
study medical monitor/designee must be consulted. Tumor assessments should 
continue as per protocol even if treatment is interrupted; 
• Confirmed diagnosis of MDS/AML; 
• Any AE, laboratory abnormality, or intercurrent illness which, in the judgment of the 
investigator, presents a substantial clinical risk to the patient with continued oral study 
treatment dosing; or 
• Patient with progressive disease. If a patient receiving study drug has met criteria for 
radiologic disease progression by RECIST v1.1 criteria but continues to derive clinical 
benefit per the investigator, continuation of treatment may be permitted after discussion 
with the sponsor (Section 5.9). 
 
8.C.6.5 
Treatment Arm C Study Drug Compliance and Accountability 
Rucaparib treatment compliance is described in Section 5.7, and M4344 compliance will be 
recorded analogously. Study drug accountability is described in Section 5.8. 
 Prior and Concomitant Therapy 
Refer to Section 6 for prior and concomitant therapy restrictions and information that is 
general across all treatment arms of this study. Additional information specific to the 
rucaparib and M4344 combination arm are described in this section. 


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8.C.7.1 
Other Concomitant Medications 
Drugs with a known risk for prolonged QT interval and Torsades de Pointes should be 
avoided. 
Because the drug interaction profile of M4344 has not yet been fully characterized, caution 
should be used when co-administration of medications with M4344. As M4344 is primarily 
metabolized by CYP3A4 and aldehyde oxidase. For this reason, concomitant administration 
with potent inhibitors or inducers of CYP3A4 should be avoided.  
• Strong CYP3A4 inhibitors include (but are not limited to): clarithromycin, itraconazole, 
ketoconazole, hepatitis C virus and HIV protease inhibitors, nefazodone, posaconazole, 
telithromycin, voriconazole, grapefruit juice 
• Strong CYP3A4 inducers include (but are not limited to): carbamazepine, rifampin, 
phenobarbital, phenytoin, St. John’s wort 
 
Caution should be used with moderate CYP3A4 inhibitors or inducers (Appendix 2). 
Alternative medications are recommended. 
Drug-drug interactions based on inhibition or induction of aldehyde oxidase have not been 
well characterized in the literature and the risk of altered drug exposure when administered 
with potent inhibitors or inducers of aldehyde oxidase is not well understood. 
The risk for M4344 as a potent perpetrator drug via inhibition or induction of CYPs, is 
predicted to be low. There is a moderate theoretical risk for transporter-mediated DDIs with 
P-gp or BCRP. M4344 and one of its metabolites have the potential to inhibit UGT1A1 at 
clinical exposures reached with twice weekly dosing (see Section 8.C.2.2). 
The solubility of M4344 is expected to decrease significantly at higher pH values. Therefore, 
concomitant administration of acid-modifying agents such as proton-pump inhibitors, H2 
receptor antagonists, and antacids should be discontinued. 
 Study Procedures and Methods for Treatment Arm C 
8.C.8.1 
Schedule of Assessments: Treatment Arm C 
Table 8.C-4 summarizes the procedures and assessments to be performed for all patients in 
Treatment Arm C (Phase 1 and Phase 2).  
Table 8.C-5 summarizes the timing of collection of PK and pharmacodynamic samples for all 
patients in Treatment Arm C.  
The investigator or their designee shall discuss with each patient the nature of the study and 
its requirements. To participate in the study, written informed consent must be obtained from 
each potential patient prior to any study activities (see Section 11.2). The information on the 
IRB/IEC approved consent form should be translated and communicated in the language the 
patient (or legally authorized representative) can understand. 


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The screening period begins with the first study-specific procedure, performed outside 
standard of care, and only after written consent for study participation has been provided. 
Additionally, patients participating in the optional tumor tissue biopsy at the time of 
radiologic disease progression/treatment discontinuation must provide additional written 
consent for this procedure.  
All procedures and assessments are to be completed within ±3 days of the scheduled time 
unless otherwise stated. 


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Table 8.C-4 Schedule of Assessments for All Patients in Treatment Arm C (Phase 1b and Phase 2) 
 
Screening Phase 
Treatment Phase 
(28-day cycles ± 3 days) 
Post Treatment Phase 
Cycles 1 and 2 
Cycles 
3+ 
Study Day 
Day -56 
to Day -1 
Day -28 
to Day -1 
Day -14 
to Day -1 
Day 1 
Day 15 
Day 1 
End of 
Treatment 
28-day Safety 
FUa 
Procedureb 
 
Informed Consent 
X 
 
 
 
 
 
 
 
Medical/Oncology History (Section 7.1)  
X 
 
 
 
 
 
 
 
Tumor Tissue Sample (Section 7.5.1)c 
X 
 
 
 
 
 
 
 
Physical Examination (Section 7.4.5)  
 
X 
 
X 
 
X 
X 
X 
Vital Signs (Section 7.4.3)  
 
X 
 
X 
X 
X 
X 
X 
12-lead ECG (Section 7.4.4)  
 
X 
 
X 
 
X 
X 
 
Prior/Concomitant 
Medications/Procedures (Section 7.2)d 
 
X 
 
X 
X 
X 
X 
X 
Disease Assessment/Tumor Scans 
(Section 7.3.1)e 
 
X 
 
 
 
X 
X 
 
ECOG Performance Status 
 
X 
 
X 
 
X 
X 
X 
Hematology (Section 7.4.2) 
 
 
X 
X 
X 
X 
X 
X 
Chemistry (Section 7.4.2) 
 
 
X 
X 
X 
X 
X 
X 
Urinalysis (Section 7.4.2) 
 
 
X 
 
 
 
 
 
Serum or plasma Pregnancy Test 
(WOCBP only) (Section 7.4.2) 
 
 
X 
X 
 
X 
X 
 
CA-125 Measurement for OC patients 
(Section 7.5.2)f 
 
 
X 
X 
 
X 
X 
 
Pharmacogenomics Blood Sample 
(Section 7.5.3)g 
 
 
 
X 
 
 
 
 


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Table 8.C-4 Schedule of Assessments for All Patients in Treatment Arm C (Phase 1b and Phase 2) 
 
Screening Phase 
Treatment Phase 
(28-day cycles ± 3 days) 
Post Treatment Phase 
Cycles 1 and 2 
Cycles 
3+ 
Study Day 
Day -56 
to Day -1 
Day -28 
to Day -1 
Day -14 
to Day -1 
Day 1 
Day 15 
Day 1 
End of 
Treatment 
28-day Safety 
FUa 
Procedureb 
 
Blood Sample for ctDNA Analysis 
(Section 7.5.2)h 
 
X 
 
X 
 
X 
X 
X 
Rucaparib and M4344 Administrationi 
 
 
 
X 
X 
X 
 
 
Adverse Eventsj (Sections 10.7 and 10.8)  
(X) 
(X) 
(X) 
X 
X 
X 
X 
X 
Post-Treatment Tumor Tissue Biopsy 
(Section 7.5.1)k 
 
 
 
 
 
 
X 
 
Blood Samples for PK 
Refer to Table 8.C-5 for sampling schedule 
 
Abbreviations: AML = acute myeloid leukemia; CA-125 = cancer antigen 125; ctDNA = circulating tumor deoxyribonucleic acid; ECG = electrocardiogram; 
ECOG = Eastern Cooperative Oncology Group; FU = Follow-up; MDS = myelodysplastic syndrome; OC = ovarian cancer; PK = pharmacokinetics; WOCBP 
= women of child-bearing potential. 
a 
Follow-up Visit (FU) should occur 28 days (±7) from the last dose of study drug, whichever is later, or can be performed on the date of discontinuation if 
that date is at least 28 days from last dose. Chemistry and hematology are only necessary at FU Visit, if toxicities are present. The follow up visit should 
be conducted in person. 
b 
The study visit window in the treatment phase is ± 3 days, unless noted otherwise for a particular assessment. Study visits should take into account the 
subject’s investigational product supply. Only 1 cycle of oral study drug will be dispensed to the subject on Day 1 of each cycle. 
c 
The tumor tissue sample must be adequate for genomic testing. If archival tissue sample is inadequate or unavailable, a more recently obtained tissue 
sample will be required prior to administration of study drug. Refer to the Laboratory Manual for details on tissue adequacy, sample collection and 
handling instructions. 
d 
Patients taking warfarin should have INR monitored regularly per standard clinical practice (Section 6.5). Patients taking digoxin should have their 
digoxin levels monitored after starting rucaparib and then regularly per standard clinical practice (Section 6.6). 
e 
Tumor scans to be performed every 8 calendar weeks (±1 week) after start of study treatment on Day 1 of Cycle 1 until radiological disease progression. 
Disease progression will be determined by RECIST v1.1. Patients with OC who meet GCIG CA-125 criteria for disease progression should have a 


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radiologic assessment and be assessed by RECIST v1.1. If the radiologic assessment does not confirm disease progression, patients should continue on 
treatment and continue to be assessed by RECIST v1.1 per the protocol schedule of assessments. 
f 
CA-125 measurement should be performed for patients with ovarian cancer at screening and on Day 1 of every subsequent cycle, at treatment 
discontinuation, as clinically indicated. If a patient discontinues treatment for reasons other than disease progression, then a sample should be taken at the 
same time as radiological imaging and ctDNA sampling. 
g 
If sample is not collected on Day 1 of Cycle 1, it should be collected as soon as possible thereafter. 
h 
Day 1 of Cycle 1 through Cycle 6 and at the same time as radiological imaging and CA-125 sampling (where feasible), at the End of Treatment, and the 
28-day Follow-up Visit. If a patient discontinues treatment for reasons other than disease progression, then a sample should be taken at the same time as 
radiological imaging and CA-125 (for ovarian cancer patients). 
i 
First dose of both study drugs in Cycle 1 should be administered within 3 days after enrollment. Administration is continuous (not just the days specified 
in the table). Refer to Section 5.5 (rucaparib) and Section 8.C.6.3 (M4344) for administration guidelines. Study treatment continues in 28-day cycles until 
disease progression, unacceptable toxicity, patient or physician request to discontinue, death, initiation of any other cancer therapy, positive pregnancy 
test, or termination of the study. 
j 
AEs, SAEs, and AESIs that occur after first administration of study drug through to 28 days after last dose of study drug(s). In addition, SAEs that were 
related to a screening procedure will also be recorded. Ongoing SAEs, AESIs, or treatment-related Grade 3/4 AEs will be followed to resolution or 
stabilization. After the Safety Follow-up, only SAEs considered as potentially study drug related (including serious reports of pneumonitis and similar 
events, ie, interstitial lung disease, pulmonary fibrosis, acute interstitial pneumonitis, alveolitis necrotizing, alveolitis, hypersensitivity pneumonitis, and 
organizing pneumonia, if considered to be related to study drug), and AESIs of MDS and AML, regardless of causality, will be recorded in the eCRF. 
k 
An optional tumor biopsy may be collected at or following disease progression until the start of the next treatment. Additional consent is required. Refer 
to the Laboratory Manual for detailed on sample collection and handling instructions. 
 
 
 


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Table 8.C-5 Pharmacokinetic and Pharmacodynamic Sample Collections in Treatment Arm C (Phase 1b and 
Phase 2) 
Study Visit 
Pharmacodynamics 
M4344 PK 
Rucaparib PK 
Cycle 1 
(Phase 1ba) 
D1b 
Predosec and  
Post-morning dose: 2.5 hrs 
Post-morning dose:  
0.5, 1, 1.5, 2.5, 4, 6 and 8 hrs 
N/A 
D15b 
Predosec and  
Post-morning dose: 2.5 hrs 
Predosec and 
Post-morning dose:  
0.5, 1, 1.5, 2.5, 4, 6 and 8 hrs 
Predosec and 
Post-morning dose:  
0.5, 1, 1.5, 2.5, 4, 6 and 8 hrs 
Cycle 2-4 
(Phase 1ba and Phase 2) 
D1 
_ 
Predosec 
Predosec 
Abbreviations: D = Day; hrs = hours; N/A = not applicable; PK = pharmacokinetics. 
a 
Phase 1b includes patients in the dose-escalation phase and the RP2D expansion. 
b 
Doses of rucaparib and M4344 must be taken at the same time on an empty stomach, ie, at least 2 hours prior and 1 hour after any meal. For Phase 1b for 
Cycle 1 Day 1 (M4344) and Day 15, a time window of ±5 minutes for specimen collections up to 2 hours and ±15 minutes from 3 to 8 hours. 
c 
Predose refers to collection prior to the morning dose of both rucaparib and M4344. The predose specimen collection should be performed within 30 
minutes before taking the next dose of study drug. 
Notes: Collection of the actual time(s) of dose administration is essential for both rucaparib and M4344 (this includes the time of the last administration before 
the D1 and D15 predose samples). 
Refer to the (Treatment Arm C) Laboratory Manual for details on sample handling and processing. 
 
 


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8.C.8.2 
Methods of Data Collection: Arm C 
See Section 7 for methods of data collection that are general across all treatment arms of this 
study. Additional information specific to the rucaparib and M4344 combination arm are 
described in this section. 
8.C.8.2.1 
Pharmacokinetic Sample Collection 
For all patients in Phase 1b and Phase 2, plasma samples are to be collected for trough level 
PK analysis of oral study drug within 1 hour before the morning dose (ie, typically within 
30 minutes prior to dosing) of rucaparib and M4344 on Day 15 of Cycle 1 (Phase 1b) and on 
Day 1 of Cycles 2, 3, and 4 (both phases). Plasma samples are to be collected approximately 
12 hours after the last oral dose of rucaparib and approximately 12 hours (BID) or 24 hours 
(QD) after the last oral dose of M4344.  
In addition, for all patients in Phase 1b, intensive PK samples will be collected for M4344 on 
Day 1 and Day 15 of Cycle 1, and for rucaparib on Day 15 of Cycle 1 (a). For Phase 1b for 
Cycle 1 Day 1 (M4344) and Day 15 (both study drugs), a time window of ±5 minutes for 
specimen collections up to 2 hours and ±15 minutes from 3 to 8 hours.  
Date and time of dose of rucaparib and M4344 are to be recorded on the eCRF for doses 
taken on PK sample days, as well as date and time for the last rucaparib and M4344 
administrations taken prior to the predose samples (both Phase 1b and Phase 2), together with 
the date/time of all plasma PK samples. 
A central laboratory will be used for bioanalysis (concentration measurements) of plasma 
rucaparib and/or M4344 and its metabolites. Please refer to the Laboratory Manual for details 
on collection and processing of blood PK samples. 
Samples obtained for PK analyses may be used for the future metabolite identification and/or 
other exploratory evaluations. 
8.C.8.2.2 
Pharmacodynamic Sample Collection 
Blood samples will be collected at the indicated time points (Table 8.C-5) for 
pharmacodynamic analyses. Biomarkers of PARP and/or ATR inhibition such as γH2AX, 
which is a biomarker associated double-strand DNA breaks, will be analyzed in these 
samples. Details on the collection, processing, and shipment of these samples are in the 
Laboratory Manual. 
 Planned Statistical Methods: Treatment Arm C 
The statistical methods that are general across treatment arms are described within 
Section 9.  
The determination of sample size for Treatment Arm C, Phase 1b and Phase 2 cohorts are 
described below. 


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8.C.9.1 
Determination of Sample Size 
The total enrollment planned for evaluation of rucaparib in combination with M4344 is 
approximately 135 patients. 
Phase 1b is based on a standard 3+3 dose-escalation design, and the overall sample size 
depends on the occurrence of safety findings, specifically, DLTs, observed at the different 
dose regimens. A minimum of 6 and maximum of approximately 55 patients across all dose 
cohorts may be enrolled. Additional patients may be enrolled to evaluate other dose levels or 
schedules as described in Section 8.C.4.2.1. Additional patients may be enrolled into a 
particular dose regimen if a patient already enrolled into that same dose regimen does not 
meet the criteria for the DLT-evaluable population, defined in Section 9.2. 
A Simon 2-stage design will be used to evaluate efficacy (confirmed overall response of CR 
or PR) of rucaparib in combination with M4344 in each of the Phase 2 cohorts. The sample 
sizes for each Phase 2 cohort were determined based on a null hypothesis (H0), which 
specifies a response proportion that if not reached (response is less than that specified), 
further investigation would not be warranted, and an alternative hypothesis (H1), which 
specifies a response proportion that if observed would warrant further investigation of the 
rucaparib and M4344 combination treatment in the corresponding cohort. 
Phase 2 Cohort C1: Ovarian Cancer Patients who have Progressed on Prior PARP 
Inhibitor Therapy 
Up to 40 patients (22 patients enrolled in Stage 1 and 18 patients enrolled in Stage 2) will be 
used to evaluate efficacy. After the first 22 patients either a) complete 16 weeks of study 
treatment or b) discontinue study treatment prior to completing 16 weeks, an interim 
(Stage 1) analysis will be performed. If ≤ 2 of these 22 patients have a confirmed overall 
response (CR or PR per investigator assessment), the sponsor and key participating 
investigators will evaluate overall benefit:risk for patients and determine whether or not to 
continue further enrollment. If 3 or more patients in Stage 1 have a confirmed overall 
response, then enrollment of the additional 18 patients will be completed. 
Characteristics of this design include: 
• H0: p ≤ 0.10; 
• H1: p ≥ 0.25; and 
• 80% power at significance level = 0.05 (one-sided). 
 
If Stage 2 is fully enrolled and ≥ 8 out of 40 total patients have a confirmed overall response, 
then per the design, the null hypothesis is rejected, and the rucaparib and M4344 combination 
warrants consideration of further investigation in patients with ovarian cancer previously-
treated with a PARP inhibitor. 


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Phase 2 Cohort C2: Patients with a Solid Tumor Associated with a Deleterious ATM 
Alteration or ATM Loss 
Up to 40 patients (22 patients enrolled in Stage 1 and 18 patients enrolled in Stage 2) will be 
used to evaluate efficacy. After the first 22 patients either a) complete 16 weeks of study 
treatment or b) discontinue study treatment prior to completing 16 weeks, an interim 
(Stage 1) analysis will be performed. If ≤ 2 of these 22 patients have a confirmed overall 
response (CR or PR per investigator assessment), then the sponsor and key participating 
investigators will evaluate overall benefit:risk for patients in both the ATM alteration and 
ATM loss subgroups and determine whether or not to continue further enrollment. If 3 or 
more patients in Stage 1 have a confirmed overall response, then enrollment of the additional 
18 patients in Stage 2 will be completed. 
Characteristics of this design include: 
• H0: p ≤ 0.10; 
• H1: p ≥ 0.25; and 
• 80% power at significance level = 0.05 (one-sided). 
 
If Stage 2 is fully enrolled and ≥ 8 out of 40 total patients have a confirmed overall response, 
then per the design, the null hypothesis is rejected, and the rucaparib and M4344 combination 
warrants consideration of further investigation in patients with a solid tumor associated with 
a deleterious ATM alteration or ATM loss. 
 
 


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9 
PLANNED STATISTICAL METHODS: ALL TREATMENT ARMS 
The statistical methods described within this section are general across treatment arms. The 
determination of sample size for each treatment arm, as well as additional analyses or 
deviations from the descriptions below are described in Section 8.X.9 of the respective 
treatment arm and/or will be described in the statistical analysis plan (SAP) for this study. 
9.1 
General Considerations 
For Phase 1b, summary tables will generally present data by dose cohort and by all patients 
enrolled. For Phase 2, summary tables will present data by expansion cohort. 
Quantitative variables will typically be summarized using frequencies and percentages for 
appropriate categorizations and may also be summarized using descriptive statistics. For 
variables summarized with descriptive statistics, the following will be presented: N, mean, 
standard deviation, median, minimum, and maximum. Categorical variables will be presented 
using frequencies and percentages.  
The Kaplan Meier methodology will be used to summarize time-to-event variables.  
Unless otherwise specified, all data will be used to their maximum possible extent but 
without any imputations for missing data. Unless otherwise specified, baseline is defined as 
the last measurement prior to the first dose of study drug.  
All statistical analyses will be conducted with the statistical analysis software (SAS®) 
System, Version 9.3 or higher. Further details around the statistical analyses planned in this 
study will be outlined in the SAP. 
9.2 
Analysis Populations  
• DLT-evaluable Population (Phase 1b): All patients in Phase 1b who have either 
received at least 80% of the planned doses of rucaparib and the second study drug (for 
Treatment Arm B, both planned infusions of the second study drug must be received) 
without having experienced a DLT or who experienced a DLT during Cycle 1. If a 
patient withdraws from the study without having met any of these criteria, then an 
additional patient will be enrolled in that dose cohort. 
• Safety Population: All patients who have received at least 1 dose of rucaparib or the 
second study drug. This will be the primary population for analyses of safety for Phase 1b 
and for each expansion cohort in Phase 2. 
• Efficacy Population: All patients who have received at least 1 dose of rucaparib or the 
second study drug and who have measurable disease per RECIST v1.1 at baseline. This 
will be the primary population for analyses of efficacy in Phase 1b and each expansion 
cohort in Phase 2. 
 


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9.3 
Demographics and Baseline Characteristics 
All demographic (eg, age, race, and ethnicity as allowed by local regulations) and baseline 
characteristics will be summarized for the Safety Population, separately for Phase 1b and 
Phase 2. The following variables, as appropriate, will be summarized with frequency 
tabulations: 
• Time since diagnosis (months): > 12 to 24, > 24 
• Baseline laboratory parameters: graded based on CTCAE 
• Molecularly defined subgroups based on HRD and other definitions as appropriate; 
• If applicable, progression-free interval following the last platinum regimen received 
(months); 0-6, > 6; 
• Number of prior anticancer regimens; also split out by 
- 
Number of prior chemotherapy regimens 
- 
Number of prior platinum-based regimens. 
 
Descriptive statistics may also be used to summarize the continuous variables. 
9.4 
Efficacy Analyses 
The analysis of all efficacy endpoints will be based on the RECIST v1.1 criteria as assessed 
by the investigator and performed using the Efficacy Population. 
9.4.1 
Efficacy Endpoints 
The primary efficacy endpoint for each expansion cohort in Phase 2: 
• Objective response.  
 
Secondary efficacy endpoints include:  
• Duration of response (DOR; Phase 2), 
• Progression-free survival (PFS; Phase 2),  
• Objective response (Phase 1b). 
 
9.4.2 
Primary Efficacy Analysis 
The primary efficacy endpoint for each expansion cohort in Phase 2 will be analyzed by 
calculating the ORR. ORR is defined as the proportion of patients with a documented and 
confirmed best overall response of CR or PR as assessed by the investigator. A confirmed 
CR or PR is a response that is maintained and documented on a subsequent tumor assessment 
no less than 4 weeks after initial response. 


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The frequency and percentages of patients with a best overall response of CR, PR, SD, or PD 
will be summarized. ORR (confirmed CR + PR) will also be summarized with frequencies 
and percentages. All summaries of response rate will be accompanied by 95% CIs. Objective 
response as a secondary endpoint for Phase 1b of the study will be analyzed in a similar 
manner as for the Phase 2 efficacy analysis. 
9.4.3 
Secondary Efficacy Analyses 
9.4.3.1 
Progression-free Survival 
PFS will be calculated as 1+ the number of days from the first dose of study drug to 
documented radiographic progression, according to RECIST v1.1, as determined by the 
investigator, or death due to any cause, whichever occurs first. Patients without a 
documented event of radiographic progression will be censored on the date of their last 
adequate tumor assessment (ie, radiologic assessment), or date of first dose of study drug if 
no post-baseline tumor assessments have been performed. Only tumor scans prior to start of 
any subsequent anticancer treatment are included. 
The Kaplan-Meier methodology will be used to summarize PFS. If able to be estimated, the 
50th (median) percentile together with a 95% CI, will be presented. The number of patients 
with events and the number of patients at risk at each timepoint will be presented, and 
censored patients will be graphically displayed. 
9.4.3.2 
Duration of Response 
For any Phase 2 patient who reached a best response of CR or PR, DOR will be measured 
from the date that best response is first recorded until the first date that PD is documented per 
RECIST v1.1. DOR will be summarized as a time to event variable. For patients who 
continue treatment post-progression, the first date of progression will be used for the 
analysis. Patients without a documented event of radiographic progression will be censored 
on the date of the last adequate tumor assessment.  
The Kaplan-Meier methodology will be used to summarize DOR. If able to be estimated, the 
50th (median) together with a 95% CI, will be presented. The number of patients with events 
and the number of patients at risk at each timepoint will be presented and censored patients 
will be graphically displayed. 
9.5 
Safety Analyses 
All safety analyses will be summarized for the Safety Population separately for each 
treatment arm. Within a treatment arm, safety analyses will be summarized by dose cohort 
and pooled for all patients in Phase 1b and by expansion cohort in Phase 2.  
Safety endpoints are incidence of AEs, clinical laboratory abnormalities, and dose 
modifications. 
AEs, clinical laboratory results, vital signs, ECG results, ECOG performance status, body 
weight, and concomitant medications/ procedures will be tabulated and summarized. 


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9.5.1 
Safety Endpoints 
The primary safety endpoint for Phase 1b is the incidence of Grade 3 or 4 AEs and clinical 
laboratory abnormalities defined as dose-limiting toxicities DLTs. 
Secondary safety endpoints (both Phase 1b and Phase 2) include the incidence of AEs, 
clinical laboratory abnormalities, vital signs, and ECG results. 
9.5.2 
Adverse Events 
Adverse events will be classified using the Medical Dictionary for Regulatory Activities 
(MedDRA) classification system. The severity of the toxicities will be graded according to 
the NCI CTCAE v5.0. TEAEs are defined as AEs with onset date on or after the date of first 
dose of study drug until 28 days after the last dose of study drug.  
The number and percentage of patients who experienced TEAEs for each SOC and preferred 
term will be presented. Multiple instances of the TEAE in each SOC and multiple 
occurrences of the same preferred term are counted only once per patient. The number and 
percentage of patients with at least one TEAE will also be summarized. 
Separate tables will be presented as follows: 
• All TEAEs; 
• TEAEs by CTCAE grade; 
• Grade 3 or greater TEAEs; 
• Treatment-related TEAEs (rucaparib and/ or second study drug); 
• Serious TEAEs; 
• Treatment-related serious TEAEs; 
• TEAEs with an outcome of death; 
• TEAEs leading to discontinuation of study drug (rucaparib and/ or second study drug); 
• TEAEs resulting in interruption/delay of study drug (rucaparib and/ or second study 
drug); and 
• TEAEs resulting in dose reduction of study drug (rucaparib and/ or second study drug). 
 
The incidence of TEAEs will be summarized by relationship to study drug (rucaparib and/ or 
second study drug) according to the following categories: “treatment-related,” or “not 
treatment-related”. If a patient experiences multiple occurrences of the same AE with 
different relationship categories for one study drug, the patient will be counted once, as a 
relationship category of treatment related.  
If a patient experiences multiple occurrences of the same AE with different toxicity grades, 
the patient will be counted once for the maximum (most severe) toxicity grade. AEs with a 


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missing toxicity grade will be presented in the summary table with a toxicity grade of 
“Missing.” For each toxicity grade, the number and percentage of patients with at least 
1 TEAE of the given grade will be summarized. 
9.5.3 
Clinical Laboratory Evaluations 
Clinical laboratory evaluations include the continuous variables for hematology and 
chemistry. The laboratory values will generally be presented in International System of Units 
(SI). The on-treatment period will be defined as the time from the first dose of study drug to 
28 days after the last dose of study drug or the last Safety Follow-up Visit, whichever is later. 
Laboratory values collected during the on-treatment period will be included in the summary 
tables. The laboratory values collected after the on-treatment period will only be presented in 
the data listings.  
The summary of laboratory data will include shift tables based on CTCAE for shifts in grade 
from baseline to maximum, minimum, and last value during the on-treatment period.  
Supporting laboratory data including normal ranges and abnormal laboratory flags will be 
provided using by-patient listings. Separate listings will be produced for clinically significant 
laboratory abnormalities (ie, those that meet Grade 3 or Grade 4 criteria according to 
CTCAE). 
9.5.4 
Vital Sign Measurements 
The on-treatment period will be defined as the time from the first dose of study drug to 
28 days after the last dose of study drug or the last Safety Follow-up Visit, whichever is later. 
Vital sign measurements collected during the on-treatment period will be included in the 
summary tables. The vital sign measurements collected after the on-treatment period will 
only be presented in the data listings.  
The summary of vital sign data will include descriptive statistics (N, mean, standard 
deviation [StD], minimum, median, and maximum) of the maximum, minimum, and last 
value during the on-treatment period. Summaries using descriptive statistics (N, mean, StD, 
minimum, median and maximum) of the change from baseline to the maximum, minimum, 
and last value during the on-treatment period will also be given. 
9.6 
Pharmacokinetic Analysis 
In the Phase 1b portion, blood sampling for PK analyses of both rucaparib and the second 
study drug will be conducted in all patients. The PK parameters will be determined using 
non-compartmental methods. Area under the curve from time zero to the last observation 
(AUC0-last) will be calculated using the trapezoid rule. The t1/2 and the AUC from time 0 to 
infinity (AUC0-inf) will be calculated from the estimated kel, as appropriate. Other parameters 
to be determined are Cmax, Cmin, tmax, Vss/F, and CL/F, which will be estimated and reported, 
as data allow. 


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9.7 
Exploratory Analysis 
Tumor tissue and blood specimens will be used for pharmacodynamic assessment of 
rucaparib and/or the second study drug activity to explore biomarkers that may be predictive 
of response or resistance to rucaparib and/or the second study drug. Biomarkers and changes 
in biomarker status may also be investigated for associations with rucaparib and/or the 
second study drug exposure and safety. 
The goal of the exploratory analyses is to assess potential relationships between biomarkers 
and the efficacy and safety of the study drug combination. The biomarkers to be evaluated 
include, but are not limited to, genomic alterations in tissue and blood, genomic LOH, other 
expression or genomic signatures, circulating growth factors and/or cytokines, and where 
applicable, PK parameters. Where possible, changes in these biomarkers from pretreatment 
to timepoints during and post-treatment will also be evaluated. Given the exploratory nature 
of these analysis, no formal hypothesis testing is planned. 
9.8 
Interim Analysis 
An interim analysis of ORR by RECIST v1.1 criteria per investigator for each Phase 2 cohort 
will be performed as specified for each treatment arm. Enrollment in the cohort may continue 
while the interim analysis is being prepared. If the continuance criteria are not met, the 
sponsor and key investigators will evaluate the overall benefit:risk for patients and provide a 
recommendation whether further enrollment should continue.  
Additionally, at any point throughout the study, the study may be terminated early due to 
unacceptable safety risk assessed by emerging data, or unacceptable toxicity observed. The 
sponsor may terminate the treatment arm or study electively or if required by regulatory 
decision. If the treatment arm or study is terminated prematurely, the sponsor will notify the 
investigators and regulatory agencies of the decision and reason for termination. Investigators 
will be required to notify the IRBs and IECs, accordingly. 
10 ADVERSE EVENT MANAGEMENT 
10.1 Definition of an Adverse Event 
An AE is defined as any untoward medical occurrence in a patient administered a medicinal 
product that does not necessarily have a causal relationship with this treatment. An AE can, 
therefore, be any unfavorable and unintended sign (including an abnormal laboratory 
finding), symptom, or disease temporally associated with the use of an investigational 
product, whether or not related to the investigational medicinal product. This includes an 
exacerbation of pre-existing conditions or events, intercurrent illnesses, drug interaction, or 
the significant worsening of the indication under investigation that is not recorded elsewhere 
on the eCRF under specific efficacy assessments. Anticipated fluctuations of pre-existing 
conditions, including the disease under study, that do not represent a clinically significant 
exacerbation or worsening are not considered AEs. 


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It is the responsibility of the investigator to document all AEs that occur during the study. 
AEs should be elicited by asking the patient a non-leading question (eg, “Have you 
experienced any new or changed symptoms since we last asked/since your last visit?”). The 
existence of an AE may be concluded from a spontaneous report of the patient; from the 
physical examination; or from special tests such as the ECG, laboratory assessments, or other 
study-specified procedure (source of AE). Symptoms reported spontaneously by the patient 
during the physical examination would also qualify as an AE (and hence documented on the 
AE eCRF, not on the physical examination eCRF, which is reserved for physical signs or 
findings). 
10.2 Definition of a Serious Adverse Event 
An SAE is any untoward medical occurrence that occurs at any dose (or, occurs after 
informed consent is given and prior to dosing if the SAE is related to a study procedure) that: 
• Results in death. Any event resulting in death during the reporting period (from date of 
first dose of study drug through 28 days after last dose of either study drug) must be 
treated as an SAE and reported as such. An event related to a study procedure that occurs 
after informed consent, but prior to dosing that results in death must also be reported as 
an SAE.  
• Is life-threatening (patient is at immediate risk of death from the event as it occurred) 
• Requires in-patient hospitalization (formal admission to a hospital for medical reasons) or 
prolongation of existing hospitalization 
• Results in persistent or significant disability/ incapacity 
• Results in a congenital anomaly or birth defect 
• Important medical events that may not result in death, are not life-threatening, or do not 
require hospitalization may be considered SAEs when, based on appropriate medical 
judgment, they may jeopardize the patient and may require medical or surgical 
intervention to prevent one of the outcomes listed in this definition. Examples of such 
events include allergic bronchospasm requiring intensive treatment in an emergency 
room or at home or the development of drug dependency or drug abuse. 
 
10.3 Definition of Adverse Events of Special Interest 
AESIs (serious or nonserious) are defined as AEs of scientific and medical concern specific 
to the sponsor’s product or program, for which ongoing monitoring and rapid communication 
by the investigator to the sponsor can be appropriate. Such an event might warrant further 
investigation in order to characterize and understand it. Depending on the nature of the event, 
rapid communication by the study sponsor to other parties (eg, regulators) might also be 
warranted. 
AESIs for rucaparib include MDS, AML and any AE of pneumonitis (including the 
following similar event terms: interstitial lung disease, pulmonary fibrosis, acute interstitial 
pneumonitis, alveolitis necrotizing, alveolitis, hypersensitivity pneumonitis, and organizing 
pneumonia). Details on AESIs for M4344 can be found in the current M4344 IB. There are 


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no specified AESIs for either lucitanib or sacituzumab govitecan within the respective IBs 
for these drugs.  
All AESIs, irrespective of causality assessment and severity, are to be reported to the sponsor 
within 24 hours (see Section 10.10 for reporting instructions).  
10.4 Events or Outcomes Not Qualifying as Serious Adverse Events 
The following are not considered SAEs and therefore do not need to be reported as such: 
• Pre-planned or elective hospitalization including social and/ or convenience situations 
(eg, respite care); 
• Hospital visits of less than 24 hours duration (eg, patient presents to the emergency room, 
but is not admitted to a ward);  
• Overdose of either study drug or concomitant medication unless associated with an SAE. 
However, the event should still be captured as a nonserious AE on the appropriate eCRF 
page; 
• Events of progression of the patient’s underlying cancer as well as events clearly related 
to progression of the patient’s cancer (signs and symptoms of progression) should not be 
reported as an AE or an SAE;  
• Events that meet the SAE criteria (as outlined in Section 10.2) and occur after informed 
consent but before the first dose of study drug, which are considered unrelated to 
screening procedures. 
 
10.5 Clinical Laboratory Assessments as Adverse Events and Serious 
Adverse Events 
It is the responsibility of the investigator to assess and document the clinical significance of 
all abnormal values as defined by the list of reference ranges from the local laboratory. In 
some cases, significant changes in laboratory values within the normal range will require 
similar judgment. 
An abnormal laboratory value that is not already associated with an AE is to be recorded as 
an AE only if any one of the following criteria is met: 
• An action on the study drug is made as a result of the abnormality; 
• Intervention for management of the abnormality is required; 
• At the discretion of the investigator should the abnormality be deemed clinically 
significant. 
 


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10.6 Pregnancy or Drug Exposure during Pregnancy 
If a patient becomes pregnant during the course of the study, study drug(s) should be held 
immediately. 
Pregnancy is not considered to be an AE or SAE; however, all pregnancies and partner 
pregnancies occurring during study participation or within 6 months of last dosing must be 
reported to the sponsor using the Pregnancy Report Form within the same timelines as for an 
SAE. 
All pregnancies will be followed through to outcome. Once the outcome of a pregnancy is 
known, the Pregnancy Outcome Report Form will be completed and reported to the sponsor. 
AEs, SAEs, or AESIs that occur during pregnancy will be assessed and processed according 
to the AE or SAE/ AESI processes using the appropriate AE or SAE/ AESI forms.   
10.7 Recording of Adverse Events, Serious Adverse Events, and 
Adverse Events of Special Interest 
Events that occur after signing of informed consent but prior to initiation of study drug(s), 
unless due to a protocol-mandated procedure, should be recorded on the Medical History 
eCRF. Any AE that occurs after first dose of study drug(s) through 28 days after receiving 
the last dose of study drug(s), will be recorded on the AE eCRF. After the 28-day reporting 
window after discontinuation of assigned treatment, only SAEs assessed as related to study 
drug(s) (including serious reports of pneumonitis and similar events, ie, interstitial lung 
disease, alveolitis, necrotizing alveolitis, hypersensitivity pneumonitis, and organizing 
pneumonia, if considered to be related to study drug), and all AESIs of MDS and AML, 
irrespective of causality, need to be reported. AEs of pneumonitis and similar events, ie, 
interstitial lung disease, pulmonary fibrosis, acute interstitial pneumonitis, alveolitis 
necrotizing, alveolitis, hypersensitivity pneumonitis, and organizing pneumonia, should only 
be reported as an AESI up to, but not beyond, the Post-treatment Follow-up Visit (28 days 
after the last dose of study drug(s). Information on the follow-up of AEs, SAEs, and AESIs is 
provided in Section 10.8. 
In order to avoid vague, ambiguous, or colloquial expressions, the AE should be recorded in 
standard medical terminology rather than the patient’s own words. Whenever possible, the 
investigator should combine signs and symptoms that constitute a single disease entity or 
syndrome into a final diagnosis, if appropriate. For example, fever, cough, and shortness of 
breath may be reported as pneumonia, if that is a reasonable diagnosis. 
Each AE is to be evaluated for causal relationship to the investigational drug(s), severity, 
and seriousness. The action taken and the outcome must also be recorded. 
SAEs and AESIs that occur during the study or within 28 days after receiving the last dose of 
study drug(s), whether or not related to study drug(s), must be reported immediately (ie, 
within 24 hours of knowledge of the event or additional information for a previously 


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reported event) to the sponsor/SAE designee. The contact information for reporting of 
SAEs/AESIs can be found on the SAE/ AESI Reporting Form.  
10.7.1 Onset Data of Adverse Events 
The onset date is the date that the event or the signs or symptoms related to the event started. 
10.7.2 Resolution Date of Adverse Events 
The resolution date is the date that the event or the signs / symptoms related to the event 
resolved or resolved with sequelae or enter the resolution date as the date when the patient 
has reached a new baseline if event is not expected to resolve. 
10.7.3 Intensity of Adverse Events 
The severity of each AE will be graded using the NCI CTCAE, v5.0 .101  
Severity is not the same as serious. 
For AEs not covered by NCI CTCAE, the severity will be characterized as mild, moderate, 
severe, life-threatening, or fatal according to the following definitions: 
• Mild events are usually transient and do not interfere with the patient’s daily activities 
• Moderate events introduce a low level of inconvenience or concern to the patient and 
may interfere with daily activities 
• Severe events interrupt the patient’s usual daily activities and hospitalization (or 
prolongation of hospitalization) may be required 
• Life-threatening events require urgent intervention to prevent death 
• Fatal events are events that lead to the patient’s death 
 
10.7.4 Causal Relationship of Adverse Events to Study Drug 
Medical judgment should be used to determine the cause of the AE considering all relevant 
factors such as, but not limited to, the underlying study indication, coexisting disease, 
concomitant medication, relevant history, pattern of the AE, temporal relationship to the 
study medication, dechallenge or rechallenge with the study drug(s) (Table 10-1).  


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Table 10-1. Causal Relationship of Adverse Events to Study Drug 
Not Related 
to Study Drug • An AE that is clearly due to extraneous causes (eg, concurrent disease, 
concomitant medications, disease under study, etc.). 
• It does not follow a reasonable temporal sequence from administration 
of the study drug. 
• It does not follow a known pattern of response to study drug. 
• It does not reappear or worsen when study drug is restarted. 
• An alternative explanation is likely, but not clearly identifiable. 
Related to 
Study Drug 
• An AE that is difficult to assign to alternative causes. 
• It follows a strong or reasonable temporal sequence from administration 
of study drug. 
• It could not be reasonably explained by the patient’s clinical state, 
concurrent disease, or other concomitant therapy administered to the 
patient.  
• It follows a known response pattern to study drug. 
• It is confirmed with a positive rechallenge or supporting laboratory 
data. 
 
10.7.5 Outcome and Action Taken 
The investigator will record the action taken and outcome for each AE according to the 
following criteria: 
Action Taken with Study Drug (note all that apply) 
• None 
• Dose reduced/delayed 
• Study drug temporarily interrupted 
• Study drug permanently discontinued 
• Other (specify) 
 
Outcome 
• Recovered 
• Recovered with sequelae 
• Recovering/ Resolving/ Improving 


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• Ongoing 
• Death 
• Lost to follow-up 
 
10.8 Follow-Up of Adverse Events, Serious Adverse Events, and 
Adverse Events of Special Interest 
All AEs (including SAEs and AESIs) occurring during the study are to be followed up in 
accordance with good medical practice until resolved; judged no longer clinically significant; 
or, if a chronic condition, until fully characterized through 28 days after the last dose of study 
drug(s). Any SAEs, AESIs, and treatment-related Grade 3/4 AEs must be followed until 
resolution or stabilization, death, or until lost to follow-up. After the 28-day window, 
treatment-related SAEs (including serious reports of pneumonitis and similar events, ie, 
interstitial lung disease, pulmonary fibrosis, acute interstitial pneumonitis, alveolitis 
necrotizing, alveolitis, hypersensitivity pneumonitis, and organizing pneumonia, if 
considered to be related to study drug), and AESIs of MDS and AML, irrespective of 
causality, need to be reported.  
10.9 Potential Drug-Induced Liver Injury 
Wherever possible, timely confirmation of initial liver-related laboratory abnormalities 
should occur prior to the reporting of a potential DILI event. All occurrences of potential 
DILIs must be reported as SAEs (see Section 10.10 for reporting details). 
Potential drug-induced liver injury is defined as:  
1. ALT or AST elevation > 3 × ULN 
AND 
2. Total bilirubin > 2 × ULN, without initial findings of cholestasis (elevated serum or 
plasma alkaline phosphatase) 
AND 
3. No other immediately apparent possible causes of ALT/AST elevation and 
hyperbilirubinemia, including, but not limited to, viral hepatitis, pre-existing chronic or 
acute liver disease, or the administration of other drug(s) known to be hepatotoxic. 
 
10.10 Regulatory Aspects of Serious Adverse Event and Adverse Events 
of Special Interest Reporting 
It is important that the investigator provide an assessment of relationship of the SAE or AESI 
to study treatment at the time of the initial report. For reporting SAEs/AESIs or pregnancies, 
use the applicable report forms. The contact information for reporting of SAEs and AESIs 
can be found on each of the forms. 


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The sponsor or its designee is responsible for submitting reports of AEs associated with the 
use of the drug that are both serious and unexpected to the US FDA, according to 21 Code of 
Federal Regulations (CFR) 312.32; to the European regulatory authorities according to the 
European Commission Clinical Trials Directive (2001/20/EC); and to other applicable 
regulatory authorities, according to national law and/or local regulations. All investigators 
participating in ongoing clinical studies with the study medication will receive copies of 
these reports for prompt submission to their IRB or IEC. In accordance with the European 
Commission Clinical Trials Directive (2001/20/EC), the sponsor or its designee will notify 
the relevant ethics committees in concerned member states of applicable suspected 
unexpected serious adverse reactions (SUSARs) as individual notifications or through 
periodic line listings. 
The sponsor or its designee will submit all safety updates and periodic reports to the 
regulatory authorities as required by applicable regulatory requirements. 
11 STUDY ADMINISTRATION 
11.1 Regulatory and Ethical Considerations 
This study will be conducted in compliance with the protocol and applicable Standard 
Operating Procedures (SOPs) and in compliance with International Council for 
Harmonisation (ICH) E6(R2); FDA regulatory requirements; and in accordance with the 
ethical principles of the Declaration of Helsinki. The ethical principles underlying European 
Union Directives 2001/20/EC, 2005/28/EC, Eudralex Volume 10, and the US Code of 
Federal Regulations, (21CFR Parts 50, 54, 56, and 312), and applicable local requirements.  
The principal investigator will assure that no deviation from, or changes to the protocol will 
take place without prior agreement from the sponsor and documented approval from the 
IRB/IEC, and local health authority (where applicable), except where necessary to eliminate 
an immediate hazard(s) to the trial patients. 
Noncompliance with the protocol, SOPs, Good Clinical Practice (GCP), and/or applicable 
regulatory requirement(s) by an investigator/institution, or by members(s) of sponsor staff or 
its representatives will lead to prompt action by the sponsor to secure compliance. If 
monitoring and/or auditing identifies serious noncompliance on the part of an 
investigator/institution, the sponsor will take steps to secure compliance or terminate the 
investigator/institutions participation in the study. When an investigator/institution’s 
participation is terminated because of noncompliance, the sponsor will promptly notify the 
regulatory authority(ies). 
All potential serious breaches of GCP must be reported to the sponsor or designee 
immediately. A serious breach is a breach of the conditions and principles of GCP in 
connection with the study or the protocol, which is likely to affect, to a significant degree, the 
safety or physical or mental integrity of the subjects of the study or the scientific value of the 
study. 


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Personnel involved in conducting this study will be qualified by education, training, and 
experience to perform their respective tasks. 
This study will not use the services of study personnel where sanctions have been invoked or 
where there has been scientific misconduct or fraud (eg, loss of medical licensure, 
debarment). 
11.1.1 
Regulatory Authority Approvals 
The sponsor or designee will submit the study protocol plus all relevant study documents to 
concerned regulatory agencies for approval prior to the study start. No patient will be 
admitted to the study until appropriate regulatory approval of the study protocol has been 
received. 
Each investigator must complete a Form FDA 1572 (or equivalent) when participating in a 
US Investigational New Drug (IND) study and provide the completed form according to 
written instructions to the sponsor (or designee). In addition, local statement of investigator 
documents must be provided where required. Each investigator must submit to the sponsor 
(or designee) financial disclosure information if required by national law and/or local 
regulations. 
The study will be registered on www.clinicaltrials.gov, European Clinical Trials Database 
(EudraCT), and other applicable study registry systems as appropriate. Data generated from 
this study must be handled in accordance with any laws, rules, and regulations related to the 
privacy of personal data or medical information applicable in the jurisdiction where the data 
is processed, including without limitation, the US Health Information Portability and 
Accountability Act of 1996 (HIPAA), and its implementing regulations, and the EU General 
Data Protection Regulation 2016/679 (GDPR). 
11.1.2 
Institutional Review Board or Independent Ethics Committee Approval 
This protocol, the IB for each study drug, and any material to be provided to the patient (such 
as advertisements, patient information sheets, or descriptions of the study used to obtain 
informed consent) must be reviewed and approved by IECs/IRBs before study start. This also 
applies to protocol amendments (note: this applies to substantial amendments in the EU).  
The sponsor will supply relevant data for the investigator to submit the study protocol and 
additional study documents to the IRB/IEC. The study protocol will be submitted review and 
approval by an IEC/ IRB, according to national law and/or local regulations, and will provide 
the IRB/IEC with all appropriate materials.  
Verification of the IEC’s/IRB’s unconditional approval of the study protocol and the written 
ICF will be transmitted to the sponsor. This approval must refer to the study by exact study 
protocol title and number, identify the documents reviewed, and state the date of the review 
and approval.  
No patient will be admitted to the study until appropriate IRB/IEC approval of the study 
protocol and ICF/patient information sheet (PIS) have been received, the investigator has 


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obtained the signed and dated informed consent form, and the eligibility criteria has been 
satisfied and confirmed.  
The principal investigator will submit appropriate reports on the progress of the study to the 
IEC/ IRB at least annually in accordance with applicable national law and/ or local 
regulations and in agreement with the policy established by the IRB/IEC and sponsor.  
The IRB/IEC must be informed by the principal investigator of all subsequent study protocol 
amendments (substantial amendments in the EU) and of SAEs or SUSARs occurring during 
the study that are likely to affect the safety of the patients or the conduct of the study, 
according to institutional policies.  
11.2 Patient Information and Consent 
All information about the clinical study, including the patient information and the ICF, is 
prepared and used for the protection of the human rights of the patient according to ICH GCP 
guidelines and the Declaration of Helsinki. 
It is the responsibility of the investigator to obtain signed ICFs from all patients participating 
in this study after adequate explanation of the aims, methods, objectives, and potential 
hazards of the study and prior to undertaking any study-related procedures.  
The ICF, prepared by the investigator with the assistance of the sponsor, must be approved 
along with the study protocol by the IRB/IEC and be acceptable to the sponsor.  
The patient must be provided with the patient information and ICF consistent with the study 
protocol version used and approved by the relevant IRB/IEC. The ICF must be in a language 
fully comprehensible to the prospective patient. Patients (and/or relatives, guardians, or 
legally-authorized representatives [where acceptable according to national law and/or local 
regulations], if necessary) must be given sufficient time and opportunity to inquire about the 
details of the study and to discuss and decide on their participation in the study with the 
investigator concerned. Both the patient and the person explaining the study and with whom 
the patient can discuss the informed consent will sign and date the ICF. A copy of the signed 
ICF will be retained by the patient and the original ICF will be filed in the investigator file 
unless otherwise agreed. The process of obtaining informed consent will should be 
documented in the patient’s source documents. The date when a patient’s informed consent 
was actually obtained will be captured in the patient’s CRF. 
11.3 Patient Confidentiality 
The investigator must assure that patients’ anonymity is strictly maintained and that their 
identities are protected from unauthorized parties. Only patient identifiers such as initials, 
year of birth, and an identification code (ie, not names) should be recorded on any form 
submitted to the sponsor and the IRB/IEC, as far as permitted by applicable local 
requirements. The investigator must record all screened and enrolled patients in the eCRF. 
The investigator must maintain a list with the identity of all treated patients, but not intended 
for use by the sponsor.  


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The investigator agrees that all information received from the sponsor or designee including, 
but not limited to, the IB, this protocol, eCRFs, the protocol specified treatment, and any 
other study information, remain the sole and exclusive property of the sponsor during the 
conduct of the study and thereafter. This information is not to be disclosed to any third party 
(except employees or agents directly involved in the conduct of the study or as required by 
law) without prior written consent from the sponsor. The investigator further agrees to take 
all reasonable precautions to prevent the disclosure by any employee or agent of the study 
center to any third party or otherwise into the public domain. 
Discontinuation of treatment does not necessarily indicate study discontinuation for a patient. 
Samples collected for research will continue to be used unless the patient explicitly 
withdraws consent for their use. If the patient withdraws consent to continue in the study or 
discontinues the study for another reason, it will be documented on the appropriate eCRF. A 
patient may withdraw consent to participate in an additional part of a study that has an 
additional consent (ie, optional tumor biopsy) yet continue to participate and be treated/ 
followed in the main part of the study. 
11.4 Study Monitoring 
On behalf of the sponsor, a contract research organization (CRO) or contract monitor will 
contact and visit the investigator at the study site prior to the entry of the first patient (unless 
the sponsor or the CRO has worked with the site recently in the same or comparable 
indication, the site location and facilities have not changed significantly, and the potential 
investigator/site are in good standing with respect to previous regulatory compliance, in such 
cases this initial visit may be waived) and at appropriate intervals during the study until after 
the last patient is completed. The monitor will also perform a study closure visit. 
Representatives from the sponsor may also contact and visit the investigators and monitor 
data during the study. 
In accordance with ICH GCP guidelines, the investigator must ensure provision of sufficient 
time, reasonable space, and adequate qualified personnel for the monitoring visits. The visits 
are for the purpose of verifying adherence to the study protocol and the completeness, 
consistency, and accuracy of data entered on the eCRF and other documents.  
The investigator will make all source data (ie, the various study records, the eCRFs, 
laboratory test reports, other patient records, drug accountability forms, and other pertinent 
data) available for the monitor and allow access to them throughout the entire study period. 
Monitoring is done by comparing the relevant site records of the patients with the entries on 
the eCRF (ie, source data verification). It is the monitor’s responsibility to verify the 
adherence to the study protocol and the completeness, consistency, and accuracy of the data 
recorded on the eCRFs; however, the principal investigator retains the ultimate responsibility 
for the quality and integrity of data generated by the site.  
By agreeing to participate in the study, the investigator agrees to cooperate with the monitor 
to ensure that any problems detected in the course of the monitoring visits are resolved. 
Contact information for the study monitor is located in the investigator file.  


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11.5 Case Report Forms and Study Data 
The data will be collected using an electronic data capture (EDC) system by remote data 
entry on eCRFs. Sites will receive training on the EDC system. All users will be supplied 
with unique login credentials. 
Data collection is the responsibility of the clinical study staff at the site under the supervision 
of the site investigator. The investigator is responsible for ensuring the accuracy, 
completeness, legibility, and timeliness of the data reported. All source documents will be 
completed in a neat, legible manner to ensure accurate interpretation of data. Data recorded 
in the eCRF should be consistent with the data recorded on the source documents. 
Prior to study start, the investigator will prepare a list showing the signature and handwritten 
initials of all individuals authorized to make or change entries on eCRFs. This “study site 
personnel and delegation list” must be kept current throughout the study. Clinical data 
(including AEs, concomitant medications, and expected adverse reactions data) and clinical 
laboratory data will be entered into a 21 CFR Part 11-compliant EDC. The data system 
includes password protection and internal quality checks, such as automatic range checks, to 
identify data that appear inconsistent, incomplete, or inaccurate. Clinical data will be entered 
directly from the source documents. This also applies to records for those patients who fail to 
complete the study. If a patient withdraws from the study, the reason must be noted on the 
eCRF. If a patient is withdrawn from the study because of a treatment-limiting AE, thorough 
efforts should be made to clearly document the outcome.  
All laboratory data and investigator observations on the results and any other clinically 
significant test results must be documented on eCRFs. 
Full information regarding EDC and completing eCRFs is included in the investigator files. 
All questions or comments related to electronic capture should be directed to the assigned 
monitor. 
11.6 Study Termination and Site Closure 
Both the sponsor and the investigator reserve the right to terminate a treatment arm and/ or 
the entire study at any time. Should this be necessary, both parties will arrange 
discontinuation procedures. In terminating all or part of the study, the sponsor and the 
investigator will assure that adequate consideration is given to the protection of the patients’ 
interests. 
The sponsor reserves the right to discontinue all or part of the study at any time for medical 
or administrative reasons. When feasible, a 30-day written notification will be given. 
A treatment arm or the entire study will be stopped if: 
• The protocol-specified treatment is considered too toxic to continue the study; 
• Evidence has emerged that, in the opinion of the sponsor or the investigator(s), makes the 
continuation of the treatment arm or study unnecessary or unethical; 


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• The stated objectives of the treatment arm or study are achieved; or 
• The sponsor discontinues the development of study medication. 
 
Regardless of the reason for termination, all data available for the patient at the time of 
discontinuation of follow-up must be recorded on the eCRF. All reasons for discontinuation 
of treatment must be documented.  
If all or part of the study is terminated prematurely, the sponsor will promptly inform the 
investigators/institutions, and the regulatory authority(ies) of the termination or suspension 
and the reason(s) for the termination or suspension. The investigators will promptly inform 
their IRB/IEC, providing the reason(s) for the termination or suspension by the sponsor or by 
the investigator/institution, as specified by the applicable regulatory requirement(s). 
11.7 Modification of the Study Protocol 
Protocol amendments, except when necessary to eliminate an immediate hazard to patients, 
must be made only with the prior approval of the sponsor. Agreement from the investigator 
must be obtained for all protocol amendments and amendments to the informed consent 
document. The IRB/IEC must be informed of all amendments (note: substantial amendments 
in the EU) and give approval prior to their implementation. The sponsor will submit any 
study protocol amendments to the concerned regulatory authorities for approval and keep the 
investigator(s) updated as detailed in the ICH GCP guidelines. 
11.8 Retention of Study Documents 
The study site will maintain a study file, which should contain all documents defined in the 
ICH E6(R2) Guidelines for GCP. The investigator should have control of all essential 
documents generated by the site. Source documents must be maintained, ALCOA-C 
(attributable, legible, contemporaneous/complete, original, accurate, and complete) used. 
Any changes to source data should be traceable, should not obscure the original entry, and 
should be explained if necessary (via an audit trail). The investigator must implement 
procedures to ensure the integrity of any data generated. 
The investigator agrees to keep records and those documents that include (but are not limited 
to) the identification of all participating patients, medical records, study-specific source 
documents, source worksheets, all original signed and dated informed consent forms, copies 
of all eCRFs, query responses, and detailed records of drug disposition to enable evaluations 
or audits from regulatory authorities and the sponsor or its designees. The investigator should 
have control of and continuous access to the eCRF data. 
The investigator shall retain records required to be maintained for a period of 5 years 
following the date a marketing application in an ICH region is approved for the drug for the 
indication for which it is being investigated or, if no application is to be filed or if the 
application is not approved for such indication, until at least 5 years after the investigation is 
discontinued. However, these documents should be retained for a longer period if required by 


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the applicable regulatory requirement(s) or if needed by the sponsor. In addition, the 
investigator must make provision for the patients’ medical records to be kept for the same 
period of time. 
No data should be destroyed without the agreement of the sponsor. Copies of original 
documents should fulfill the requirements for certified copies. Should the investigator wish to 
assign the study records to another party or move them to another location, the sponsor must 
be notified in writing of the new responsible person and/or the new location. The sponsor 
will inform the investigator, in writing, when the study-related records are no longer needed. 
All clinical study information should be recorded, handled and stored in a way that allows 
accurate reporting, interpretation and verification, irrespective of the media used. 
The sponsor and the investigator will maintain a record of the location(s) of their respective 
essential documents including source documents. The storage systems used during the study 
and for archiving (irrespective of media used) must provide for documentation identification, 
version history, search and retrieval. 
Patients’ medical records and other original data will be archived in accordance with the 
archiving regulations or facilities of the investigational site. 
11.9 Quality Control and Assurance 
The sponsor will implement and maintain quality control and quality assurance procedures 
with written standard operating procedures to ensure that the study is conducted, and data are 
generated, documented, and reported in compliance with the protocol, GCP, and applicable 
regulatory requirements.  
Aspects of the study that are essential to ensure human subject protection and reliability of 
study results should be the focus of these procedures. 
11.9.1 
Changes to the Protocol and Deviations 
The investigator may not deviate from the protocol unless necessary to eliminate immediate 
hazards to the patient. A deviation may result in the patient having to be withdrawn from the 
study and rendering that patient nonevaluable. Any deviation must be documented in the 
source documents and reported to the sponsor.  
11.9.2 
Study Site Training and Ongoing Monitoring 
Each investigator and the site personnel for this study will be trained by the sponsor and/ or a 
designee (ie, a CRO) on the design, conduct, procedures, and administrative aspects of this 
study. This may include, but is not limited to, on-site training, Investigator Meeting(s), 
and/ or tele/ videoconferencing. Training may be ongoing as refresher, to address specific 
items, or to introduce changes in the study.  
In accordance with Code of Federal Regulations 21 CFR 312.56, ICH GCP E6(R2), 
2001/20/EC, 2005/28/EC, and local regulations, the clinical monitor will periodically inspect 


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via direct access to records, all eCRFs, study documents, medical records (office, clinic, or 
hospital) for patients in this study (anonymity is to be preserved), research facilities, and 
clinical laboratory facilities associated with this study at mutually convenient times during 
and after completion of the study. If these requirements are in conflict with local regulatory 
restrictions or institutional requirements, the investigator must inform the sponsor of these 
restrictions before initiation of the study. 
11.9.3 
Direct Access to Source Data/ Documents for Audits and Inspections 
The sponsor and investigator sites are to maintain a record of locations of essential 
documents and study source documents. The storage systems used during the study and for 
archiving (irrespective of media used) must provide for documentation identification, version 
history, search, and retrieval. Members of the sponsor’s GCP Quality Assurance Department 
or designees may conduct an audit of a clinical site at any time during or after completion of 
the study. The investigator will be informed if an audit is to take place and advised as to the 
scope of the audit. Inspections and audits are typically carried out during the clinical and 
reporting phases of this study to ensure that the study is conducted and data are generated, 
documented, and reported in compliance with the protocol, GCP, written SOPs and 
applicable laws, rules, and regulations. 
Representatives of the FDA, European Medicines Agency (EMA), or other regulatory 
agencies, including IRB/IEC representatives may also conduct an audit or inspection of the 
study. If informed of such an activity, the investigator should notify the sponsor immediately. 
The investigator will ensure that the auditors and inspectors have access to the clinical 
supplies, study site facilities, and laboratory, and that all data (including original source 
documentation) and all study files and electronic records are available, if requested. 
11.10 Clinical Study Report 
A clinical study report (CSR) will be prepared, regardless of whether the study is completed 
or terminated early, under the responsibility and supervision of the sponsor and signed by the 
sponsor’s chief medical officer, head of biostatistics, and head of regulatory affairs; thereby 
indicating their agreement with the analyses, results, and conclusions of the CSR. The CSR 
will be provided to the regulatory agency(ies) as required by the applicable regulatory 
requirements. 
11.11 Publication and Disclosure Policy 
All data generated from this study will be maintained by the sponsor. All data generated from 
this study, and all information furnished by the sponsor, the investigators, and other 
participating study groups shall be held in strict confidence. Independent analysis and/or 
publication of these data by the investigator(s) or any member of their staff are not permitted 
without the prior written consent of the sponsor. Any collaborative publications will be 
authored in accordance with the applicable guidelines (eg, International Committee of 
Medical Journal Editors [ICJME]).102 Written permission to the investigator will be 
contingent on the review of the statistical analysis and manuscripts/abstract by the sponsor 
and participating cooperative groups, and will provide for nondisclosure of the sponsor and 


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cooperative groups confidential or proprietary information. In all cases, the parties agree to 
provide all manuscripts or abstracts to all other parties 60 days prior to submission. This will 
enable all parties to protect proprietary information and to provide comments based on 
information that may not yet be available to other parties.  
11.12 Investigator Oversight 
The investigator has a responsibility for supervising any individual or party to whom they 
delegate study related duties or functions conducted at the study site. This includes the 
services of any party or individual retained by the investigator for this purpose. All staff 
delegated study responsibilities must be documented on an approved Delegation of Authority 
log for the study and this filed with the essential documents. In addition, the investigator 
must ensure that delegated staff are qualified by training, experience and licensure (as 
applicable). The investigator should implement procedures to ensure integrity of the 
study-related duties, functions performed, and any data generated. 
 


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activation but synergizes with p53 in the replication checkpoint. J Biol Chem. 
2002;277(6):4428-34. 
92. Sangster-Guity N, Conrad BH, Papadopoulos N, Bunz F. ATR mediates cisplatin 
resistance in a p53 genotype-specific manner. Oncogene. 2011;30(22):2526-33. 
93. Nghiem P. ATR inhibition selectively sensitizes G1 checkpoint-deficient cells to lethal 
premature chromatin condensation. Proc Natl Acad Sci U S A. 2001;98(16):9092-7. 
94. Gilad O, Nabet BY, Ragland RL, Schoppy DW, Smith KD, Durham AC, et al. 
Combining ATR suppression with oncogenic Ras synergistically increases genomic 
instability, causing synthetic lethality or tumorigenesis in a dosage-dependent manner. 
Cancer Research. 2010;70(23):9693-702. 
95. Schoppy DW, Ragland RL, Gilad O, Shastri N, Peters AA, Murga M, et al. Oncogenic 
stress sensitizes murine cancers to hypomorphic suppression of ATR. J Clin Invest. 
2012;122(1):241-52. 
96. Murga M, Campaner S, Lopez-Contreras AJ, Toledo LI, Soria R, Montana MF, et al. 
Exploiting oncogene-induced replicative stress for the selective killing of Myc-driven 
tumors. Nat Struct Mol Biol. 2011;18(12):1331-5. 
97. Hammond EM, Dorie MJ, Giaccia AJ. Inhibition of ATR leads to increased sensitivity to 
hypoxia/reoxygenation. Cancer Research. 2004;64(18):6556-62. 
98. Pires IM, Olcina MM, Anbalagan S, Pollard JR, Reaper PM, Charlton PA, et al. 
Targeting radiation-resistant hypoxic tumour cells through ATR inhibition. Br J Cancer. 
2012;107(2):291-9. 
99. Kim H, George E, Ragland R, Rafial S, Zhang R, Krepler C, et al. Targeting the 
ATR/CHK1 Axis with PARP Inhibition Results in Tumor Regression in BRCA-Mutant 
Ovarian Cancer Models. Clin Cancer Res. 2017;23(12):3097-108. 
100. Cimprich KA, Cortez D. ATR: an essential regulator of genome integrity. Nat Rev Mol 
Cell Biol. 2008;9(8):616-27. 
101. US Department of Health and Human Services, National Institutes of Health, National 
Cancer Institute. Common Terminology Criteria for Adverse Events (CTCAE), Version 
5.0 27 November 2017 [Available from: 
https://ctep.cancer.gov/protocolDevelopment/electronic_applications/docs/CTCAE_v5_
Quick_Reference_8.5x11.pdf. 
102. International Committee of Medical Journal Editors. Recommendations for the Conduct, 
Reporting, Editing, and Publication of Scholarly Work in Medical Journals December 
2017 [Available from: http://www.icmje.org/recommendations/. 
103. Cockcroft DW, Gault MH. Prediction of creatinine clearance from serum creatinine. 
Nephron. 1976;16(1):31-41. 
104. US Food and Drug Administration. Drug Development and Drug Interactions: Table of 
Substrates, Inhibitors and Inducers  [updated 14 November 2017. Available from: 
https://www.fda.gov/Drugs/DevelopmentApprovalProcess/DevelopmentResources/Drug
InteractionsLabeling/ucm093664.htm. 
 
 


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13 APPENDICES 
Appendix 1 
Cockcroft-Gault Formula 
Estimated Glomerular Filtration Rate (GFR) 
Estimated GFR using serum creatinine value is at screening and may be collected each time 
clinical chemistry testing occurs. 
Male CLcr = 
(140 – age) × Body Weight (kg) 
 
 
72 × Serum Creatinine 
 
Female CLcr = (140 – age) × Body Weight (kg) × 0.85 
 
 
72 × Serum Creatinine 
 
This formula expects weight to be measured in kilograms and creatinine to be measured in 
mg/dL; the calculated units are mL/min.103 
When serum creatinine is measured in µmol/L: 
 
 
Where Constant is 1.23 for men and 1.04 for women. 
 
 
 
 


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Appendix 2 
Example Inhibitors and Inducers of CYP2C8 and 
CYP3A4 (not an inclusive list) 
CYP Enzyme 
Strong Inhibitor 
(Contraindicated) 
Moderate Inhibitor 
(Use with Caution) 
CYP2C8 
gemfibrozil 
teriflunomide 
CYP3A 
boceprevir 
clarithromycin 
cobicistat 
conivaptan 
danoprevir and ritonavir 
diltiazem 
grapefruit juicea 
idelalisib 
indinavir and ritonavir 
itraconazole 
ketoconazole 
lopinavir and ritonavir 
paritaprevir and ritonavir and 
(ombitasvir and/or dasabuvir) 
nefazodone 
nelfinavir 
posaconazole 
ritonavir 
saquinavir and ritonavir 
telaprevir 
tipranavir and ritonavir 
troleandomycin 
voriconazole 
aprepitant 
cimetidine 
ciprofloxacin 
clotrimazole 
crizotinib  
cyclosporine 
dronedarone 
erythromycin 
fluconazole 
erythromycin 
imatinib 
tofisopam 
verapamil 
CYP Enzymes 
Dual Inhibitor 
(Contraindicated) 
Dual Inhibitor 
(Use with Caution) 
CYP3A and 
CYP2C8 
clopidogrel 
verapamil 
teriflunomide 
trimethoprim 
ticargrelor 


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CYP Enzyme 
Strong Inducer (Contraindicated) 
CYP3A 
carbamazepine 
enzalutamide 
mitotane 
phenytoin 
rifampin 
St. John’s Wort 
Source: US Food and Drug Administration. Drug Development and Drug Interactions: Table of 
Substrates, Inhibitors and Inducers104 
a 
The effects of grapefruit juice vary widely among brands, thus can be classified as both a strong and 
moderate inhibitor depending on concentration, quantity consumed, and preparation. Patients should 
be advised to avoid. 
 

SAP_001.pdf: 
STATISTICAL ANALYSIS PLAN 
SEASTAR: A Phase 1b/2, Open-label, Parallel Arm Study to Assess the 
Safety, Tolerability, Pharmacokinetics, and Preliminary Efficacy of Oral 
Rucaparib in Combination with Other Anticancer Agents in Patients with a 
Solid Tumor 
Arm A: rucaparib and lucitanib 
PROTOCOL NUMBER: 
CO-338-098 
VERSION: 
1.0 
DATE FINAL: 
10 September 2021 
SPONSOR: 
Clovis Oncology, Inc. 
 
 
CONFIDENTIAL 
The information contained in this document is regarded as confidential 
and, except to the extent necessary to obtain informed consent, may not be 
disclosed to another party unless such disclosure is required by law or 
regulations. Persons to whom the information is disclosed must be 
informed that the information is confidential and may not be further 
disclosed by them. 
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Approval Page 
 
 
  
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TABLE OF CONTENTS 
TABLE OF CONTENTS ...........................................................................................................3 
LIST OF IN-TEXT TABLES ....................................................................................................4 
LIST OF APPENDICES ............................................................................................................4 
ABBREVIATIONS AND SPECIALIST TERMS ....................................................................5 
1 
INTRODUCTION ...........................................................................................................7 
2 
OVERALL STUDY DESIGN, OBJECTIVES, AND ENDPOINTS .............................7 
2.1 
Study Design ............................................................................................................7 
2.2 
Study Objectives and Endpoints ..............................................................................8 
2.3 Sample Size Justification ...............................................................................................9 
3 
GENERAL ANALYSIS CONVENTIONS ....................................................................9 
3.1 
Analysis Populations ................................................................................................9 
4 
PATIENT DISPOSITION ...............................................................................................9 
5 
PROTOCOL DEVIATIONS .........................................................................................10 
6 
DEMOGRAPHICS AND BASELINE CHARACTERISTICS ....................................10 
6.1 
Demographics ........................................................................................................10 
6.2 
Baseline Clinical Characteristics ...........................................................................10 
6.3 
Medical History .....................................................................................................10 
7 
DOSE-LIMITING TOXICITIES ..................................................................................10 
8 
STUDY DRUG EXPOSURE AND COMPLIANCE ...................................................11 
9 
PRIOR AND CONCOMITANT MEDICATIONS ......................................................11 
10 
EFFICACY ANALYSIS ...............................................................................................11 
11 
EXPLORATORY ANALYSIS .....................................................................................12 
12 
PHARMACOKINETIC ANALYSIS ...........................................................................12 
13 
SAFETY ANALYSIS ...................................................................................................12 
13.1 
Adverse Events ......................................................................................................12 
13.2 
Clinical Laboratory Evaluations ............................................................................13 
13.3 
Vital Signs ..............................................................................................................13 
14 
STATISTICAL / ANALYTICAL ISSUES ..................................................................14 
14.1 
Handling of Dropouts or Missing Data ..................................................................14 
14.2 
Pooling of Centers in Multi-Center Studies ...........................................................14 
14.3 
Multiple Comparison / Multiplicity .......................................................................14 
14.4 
Examination of Subgroups .....................................................................................14 
14.5 
Interim Analyses and Data Monitoring..................................................................14 
15 
REFERENCES ..............................................................................................................15 
16 
APPENDICES ...............................................................................................................16 
 
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LIST OF IN-TEXT TABLES 
Table 1. 
Primary, Secondary, and Exploratory Objectives and Endpoints for Phase 1b ................... 8 
LIST OF APPENDICES 
Appendix 1 
Response Evaluation Criteria in Solid Tumors ...................................................... 16 
 
 
 
 
 
 
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ABBREVIATIONS AND SPECIALIST TERMS 
AE(s) 
adverse event(s) 
ALT 
alanine aminotransferase 
ANC 
absolute neutrophil count 
AST 
aspartate aminotransferase 
AUC0-last 
last quantifiable concentration 
BID 
twice daily 
CL/F 
plasma clearance 
Cmax 
maximum observed concentration 
Cmin 
minimum concentration 
CR 
complete response 
CRM 
cohort review meeting 
CSR 
clinical study report 
CTCAE 
Common Terminology Criteria for Adverse Events 
ctDNA 
circulating cell-free tumor DNA 
DBP 
diastolic blood pressure 
DLT 
dose limiting toxicity 
DOR 
duration of response 
ECOG 
Eastern Cooperative Oncology Group 
MTD 
maximum tolerated dose 
NCI 
National Cancer Institute 
ORR 
objective response per RECIST 
PD 
progressive disease 
PK 
pharmacokinetic(s) 
PR 
partial response 
QD 
once daily 
RECIST 
Response Evaluation Criteria in Solid Tumors 
RP2D 
Recommended Phase 2 dose 
SAP  
statistical analysis plan 
SBP 
Systolic blood pressure 
SD 
stable disease 
SI 
International System of Units 
StD 
standard deviation 
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TEAE 
treatment-emergent adverse event 
Tmax 
time to maximum concentration 
ULN 
upper limit of normal 
 
 
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1 INTRODUCTION 
This SAP describes the data summaries and any statistical analyses to be performed to assess 
the safety, efficacy, and pharmacokinetics (PK) of rucaparib (CO-338) for Clovis Oncology, 
Inc sponsored clinical study CO-338-098, entitled “SEASTAR: A Phase 1b/2, Open-label, 
Parallel Arm Study to Assess the Safety, Tolerability, Pharmacokinetics, and Preliminary 
Efficacy of Oral Rucaparib in Combination with Other Anticancer Agents in Patients with a 
Solid Tumor.”  
 
This SAP addresses only the Phase 1b portion of Arm A of the study. The study reached the 
maximum rucaparib dose of 600 mg BID and a lucitanib dose of 6 mg QD. While the 
maximum tolerated dose (MTD) was not defined, the study was closed to further enrollment. 
The study will not continue to Phase 2 due to a change in priorities and no further clinical 
development of the lucitanib plus rucaparib combination is planned at this time. The analysis 
plan is therefore reduced from what was indicated in the protocol in order to support a 
abbreviated CSR. Results for Arm B of the Ph 1b part of the study are analyzed under a 
different SAP.  
2 OVERALL STUDY DESIGN, OBJECTIVES, AND ENDPOINTS 
2.1 STUDY DESIGN 
For the Phase 1b portion of Arm A, the plan estimated 6 to 12 dose-escalation cohorts, with a 
minimum of 3 patients enrolled in each cohort, followed by an expanded evaluation of the 
recommended phase 2 dose (RP2D) in up to 10 additional patients. Dose escalation was to 
follow a 3+3 design.  
 
The initial combination dose consisted of oral rucaparib 300 mg BID and oral lucitanib 4 mg 
QD, both administered continuously. In the initial program, the dose of rucaparib was to be 
escalated in 100 mg BID increments up to a maximum of 600 mg BID. A later protocol 
amendment allowed the final rucaparib dose to escalate from 400 to 600 mg BID. The dose 
of lucitanib was to be escalated in increments of 2 mg, up to a maximum dose of 10 mg QD. 
 
 
 
 
 
 
 
 
 
 
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2.2 STUDY OBJECTIVES AND ENDPOINTS 
Because this study was terminated early, not all endpoints from the protocol will be analyzed. 
Table 1 outlines the objectives and endpoints planned per protocol for Phase 1b of Arm A. 
The final column includes the analyses to be included in the CSR. 
Table 1. 
Primary, Secondary, and Exploratory Objectives and Endpoints for 
Phase 1b 
Primary Objectives 
Primary Endpoints 
Included in CSR 
To evaluate the safety and tolerability of 
rucaparib in combination with lucitanib and to 
determine the MTD and/or the RP2D of the 
combination. 
Incidence of AEs, clinical 
laboratory abnormalities, dose 
modifications, and blood pressure 
Yes: AEs, some 
clinical 
laboratories, and 
dose modifications 
will be included 
Secondary Objectives 
Secondary Endpoints 
 
To characterize the PK of rucaparib and 
lucitanib when agents are co-administered. 
Area under the curve from time 
zero to the last quantifiable 
concentration (AUC0-last), 
maximum observed concentration 
(Cmax), time to maximum 
concentration (Tmax), and apparent 
plasma clearance (CL/F)  
Not included in 
CSR 
To evaluate the preliminary efficacy of 
rucaparib in combination with lucitanib in 
various solid tumors. 
Objective response per RECIST 
v1.1 (ORR) 
Yes 
Exploratory Objectives 
Exploratory Endpoints 
 
To assess tumor tissue biomarkers that 
correlate with response to the combination. 
Not defined in protocol 
Not included in 
CSR 
To evaluate circulating cell-free tumor DNA 
(ctDNA) as a molecular marker of response 
to the combination. 
Not defined in protocol 
Not included in 
CSR 
To evaluate biomarkers associated with 
resistance to the combination. 
Not defined in protocol 
Not included in 
CSR 
To assess genomic changes over time in 
plasma and tumor samples. 
Not defined in protocol 
Not included in 
CSR 
To determine steady-state exposure of 
rucaparib and lucitanib by sparse PK 
sampling. 
Plasma concentration at trough 
(Cmin) 
Yes 
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2.3 SAMPLE SIZE JUSTIFICATION 
For Arm A Phase 1b, it was estimated that up to 55 patients would be enrolled following a 
standard 3+3 design, dependent upon the occurrence of safety findings, specifically dose 
limiting toxicities (DLTs), observed at the different dose levels. Nineteen subjects were 
enrolled before the study was terminated. 
3  GENERAL ANALYSIS CONVENTIONS 
Quantitative variables will typically be summarized using frequencies and percentages for 
appropriate categorizations and may also be summarized using descriptive statistics. For 
variables summarized with descriptive statistics, the following will be presented: N, mean, 
standard deviation (StD), median, minimum, and maximum. Categorical variables will be 
presented using frequencies and percentages.  
Baseline is defined as the last measurement on or prior to the first dose of rucaparib 
administration, unless otherwise specified.  
All statistical analyses will be conducted with the SAS® System, Version 9.4 or higher.  
3.1 ANALYSIS POPULATIONS 
The following analysis populations are defined for the study: 
Safety Population: All patients who have received at least 1 dose of rucaparib or lucitanib. 
 
DLT-evaluable Population: All patients in Phase 1b who have either received at least 80% 
of the planned doses of rucaparib and lucitanib without having experienced a DLT or who 
experienced a DLT during Cycle 1. If a patient withdrew from the study without having met 
any of these criteria, then an additional patient was enrolled in that dose cohort. 
 
Efficacy Population: All patients who have received at least 1 dose of rucaparib or lucitanib 
and who have measurable disease per RECIST v1.1 at baseline. 
 
PK-Evaluable Population: all patients who have received at least one dose of rucaparib or 
lucitanib and have had at least one measurable concentration. 
4 PATIENT DISPOSITION 
Patient disposition will be summarized using frequency counts and the corresponding 
percentages. The number of patients in each analysis population, number of patients 
discontinued, and the primary reason for treatment discontinuation will be summarized.
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5 PROTOCOL DEVIATIONS 
The number of patients with major protocol deviations (eg, inclusion or exclusion criteria) 
will be determined prior to data base lock and will be summarized with frequencies and 
percentages or provided in a patient listing. 
Protocol deviations will not be used to exclude any patients from the efficacy analyses. 
6 DEMOGRAPHICS AND BASELINE CHARACTERISTICS 
All demographics will be summarized for the safety population. 
6.1 DEMOGRAPHICS 
The demographic variables will be summarized with frequency tabulations and descriptive 
statistics. The demographic variables presented will include age, height, weight and sex using 
the following categorizations: 
• Age (years): ≤ 50, 51-60, 61-70, 71-80, 81-90, > 90; 
• Height (cm): ≤ 75, > 75-100, > 100-125, > 125-150, > 150-175, > 175; 
• Weight (kg): ≤ 50, > 50-75, > 75-100, > 100-125, > 125-150, > 150 
• Sex: Male, Female 
• Race: American Indian or Alaskan Native, Asian, Black or African American, Native 
Hawaiian or Pacific Islander, White 
• Ethnicity: Hispanic or Latino, Not Hispanic or Latino 
• Baseline ECOG: 0,1 
6.2 BASELINE CLINICAL CHARACTERISTICS 
HRD status will be listed. 
6.3 MEDICAL HISTORY 
Medical history events will not be analyzed. 
7 DOSE-LIMITING TOXICITIES 
A summary of the number of DLTs by dose level and a patient listing of all DLTs will be 
provided for the patients in the DLT-evaluable population. A DLT for Arm A is defined at 
any of the following events occurring in Cycle 1, according to Common Terminology 
Criteria for Adverse Events (CTCAE) version 5.0: 
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 Grade 3 or greater febrile neutropenia (i.e., fever > 38.3°C with Absolute Neutrophil 
Count (ANC) < 1.0 × 109/L) of any duration; 
 Grade 3 thrombocytopenia (platelets < 50 × 109/L) with significant bleeding or Grade 
4 thrombocytopenia (platelets < 25 × 109/L) ≥ 5 days duration;; 
 Grade 4 anemia (i.e., life-threatening consequences; urgent intervention indicated) or 
any anemia (regardless of grade or severity) requiring a blood transfusion; 
 Hypertension, defined as systolic blood pressure [SBP] ≥ 160 mmHg and/or diastolic 
blood pressure [DBP] ≥ 100 mmHg, that does not resolve to ≤ Grade 2 within 14 days 
despite optimized antihypertensive therapy, or any Grade 4 hypertension 
(hypertension with life-threatening consequences); 
 Any nonhematological AE ≥ Grade 3, with the exception of: 
o Nausea, vomiting, and diarrhea if well controlled by systemic medication and 
with duration ≤ 48 hrs; 
o Fatigue; 
o Hyponatremia; 
o Grade 3 alanine aminotransferase (ALT) or aspartate aminotransferase (AST) 
not accompanied by a concomitant increase in total bilirubin above the upper 
limit of normal (ULN). Note: any Grade 4 ALT/AST is a DLT. 
8 STUDY DRUG EXPOSURE AND COMPLIANCE 
The following variables will be summarized: 
 Duration of treatment (days) 
 Duration of treatment (months) 
 Number of cycles started 
 Number of dose reductions 
 Number of treatment interruptions 
 Dose intensity 
Duration of treatment will be calculated as 1+ the number of days from earliest study drug 
start date to date of last study drug discontinuation. Dose intensity will be calculated as the 
actual dose received divided by the assigned dose amount. Descriptive statistics and 
frequencies/percentages for appropriate categorizations will be used to summarize study drug 
exposure variables. 
9 PRIOR AND CONCOMITANT MEDICATIONS 
Prior and concomitant medications will not be analyzed in the CSR.  
10  EFFICACY ANALYSIS 
Efficacy analyses will be performed using the efficacy population. 
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Overall objective response to treatment according to RECIST v1.1 as assessed by the 
investigator will be listed along with target lesion measurements and response, non-target 
lesion response, and assessment of new lesions. Confirmation of a complete response (CR) or 
partial response (PR) is a response that is maintained and documented on a subsequent tumor 
assessment no less than 4 weeks after initial response. Duration of response (DOR) will also 
be calculated as the time from the date that a confirmed PR or CR is first recorded until the 
first date that progressive disease (PD) is documented per RECIST v1.1. Duration of stable 
disease (SD) will be calculated from the start of treatment to the first PD if the subject had a 
best response of SD. 
 
A listing of all tumor scan details collected in the clinical database, including assessment of 
objective response and DOR will be provided. 
11  EXPLORATORY ANALYSIS 
Only the PK exploratory endpoint will be analyzed in the CSR. In all patients with at least 
one PK sample collected, the trough plasma rucaparib and lucitanib PK data (Cmin), summary 
statistics of Cmin (N, mean, SD, minimum, median, max, CV%), and the mean (SD) 
concentration versus time plot will be reported.  
12 PHARMACOKINETIC ANALYSIS 
The secondary PK analytical plan and analyses will be included in a separate PK report.   
13 SAFETY ANALYSIS 
The safety analyses will be performed using the safety population. 
13.1  ADVERSE EVENTS 
AEs will be classified using the MedDRA v. 24.0 classification system. The severity of the 
toxicities will be graded according to the National Cancer Institute (NCI) CTCAE v5.0 
whenever possible. TEAEs are defined as AEs with onset date on or after the date of first 
dose of study medication until the date of the last study medication dose plus 28 days. 
Adverse events will be considered treatment-emergent if all or part of the date of onset of the 
AE is missing and it cannot be determined if the AE meets the definition for treatment-
emergent. 
The number and percentage of patients who experienced TEAEs for each system organ class 
and preferred term will be presented. Multiple instances of the TEAE in each system organ 
class and multiple occurrences of the same preferred term are counted only once per patient. 
The number and percentage of patients with at least one TEAE will also be summarized.   
The incidence of TEAEs will also be summarized by relationship to study drug according to 
the following categories: “treatment-related,” or “not treatment-related” for each study drug. 
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If a patient experiences multiple occurrences of the same AE with different relationship 
categories, the patient will be counted once, as a relationship category of treatment-related.   
If a patient experiences multiple occurrences of the same AE with different toxicity grades, 
the patient will be counted once for the maximum (most severe) toxicity grade. AEs with a 
missing toxicity grade will be presented in the summary table with a toxicity grade of 
“Missing.” For each toxicity grade, the number and percentage of patients with at least one 
TEAE of the given grade will be summarized.    
Separate tables will be presented including but not limited to: 
• All TEAEs; 
• TEAEs by CTCAE grade; 
• Grade 3 or greater TEAEs; 
• Treatment-related TEAEs will be included in the following three categories of 
relatedness: related to rucaparib, related to lucitanib and related to either study drug. 
Relatedness will be analyzed, overall and by categories: CTCAE grade, grade 3 or 
greater, serious TEAEs, resulting in dose reduction, resulting in dose interruption, 
resulting in dose discontinuation, outcome of death; 
• Serious TEAEs; 
• TEAEs with an outcome of death; 
• TEAEs leading to discontinuation of rucaparib only, lucitanib only, or either study drug; 
• TEAEs resulting in interruption of rucaparib only, lucitanib only, or either study drug; 
and 
• TEAEs resulting in reduction, delay, or interruption of rucaparib only, lucitanib only, or 
either study drug. 
13.2 CLINICAL LABORATORY EVALUATIONS 
Clinical laboratory evaluations include the continuous variables for hematology, chemistry, 
and urinalysis. The laboratory values will generally be presented in International System (SI) 
units. The on-treatment period will be defined as the time from earliest first dose to 28 days 
after the last dose of rucaparib or lucitanib, whichever is last. Hematology, chemistry and 
urinalysis values collected will be listed. Descriptive summaries, and all chemistry and 
urinalysis parameters, mentioned in the protocol will not be included in the analysis.    
13.3 VITAL SIGNS 
The on-treatment period will be defined as the time from first dose to 28 days after the last 
dose of study drug. Blood pressure measurements (systolic and dystolic) collected during the 
on-treatment period will be included in the summary tables. The blood pressure 
measurements collected after the on-treatment period will only be presented in the data 
listings.   
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The summary of blood pressure data will include descriptive statistics (N, mean, StD, 
minimum, median, and maximum) of the maximum, minimum, and last value during the on-
treatment period. Summaries using descriptive statistics (N, mean, StD, minimum, median, 
and maximum) of the change from baseline to the maximum, minimum, and last value during 
the on-treatment period will also be given. The data will be presented separately for each 
treatment group and overall.  
14 STATISTICAL / ANALYTICAL ISSUES 
14.1  HANDLING OF DROPOUTS OR MISSING DATA 
All data will be used to their maximum possible extent, but without any imputations for 
missing data.  
14.2  POOLING OF CENTERS IN MULTI-CENTER STUDIES 
All centers will be pooled for analysis. 
14.3  MULTIPLE COMPARISON / MULTIPLICITY 
No statistical comparisons will be performed. 
14.4  EXAMINATION OF SUBGROUPS 
Analyses of primary and secondary endpoints may be analyzed by starting dose. No 
additional subgroup analyses will be performed. 
14.5  INTERIM ANALYSES AND DATA MONITORING 
No formal interim analyses occurred outside standard Cohort Review Meetings (CRM). 
CRMs were held for the first 4 dose cohorts.  
14.6 ANALYSIS INCLUDED ON CT.GOV 
Because enrollment was halted early with less than 20 subjects enrolled, only the primary 
endpoint will be included in CT.gov analyses  
 
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15  REFERENCES 
1. Eisenhauer EA, Therasse P, Bogaerts J, Schwartz LH, Sargent D, Ford R, et al. New response 
evaluation criteria in solid tumours: revised RECIST guideline (version 1.1). Eur J Cancer. 
2009;45(2):228-47. 
 
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16 APPENDICES 
Appendix 1 
Response Evaluation Criteria in Solid Tumors 
The RECIST guidelines (Version 1.1) are described in Eisenhauer (2009)1 and at 
http://www.eortc.be/Recist/Default.htm. A short summary is given below. 
Measurable Disease: 
Tumor lesions: measurable lesions are defined as those that can be accurately measured in at 
least 1 dimension (longest diameter to be recorded) with the following: 
 A minimum size of 10 mm by CT scan (CT scan thickness no greater than 5 mm). 
 A minimum size of 10 mm caliper measurement by clinical exam (lesions that cannot be 
accurately measured with calipers should be recorded as nonmeasurable). 
 A minimum size of 20 mm by chest X-ray. 
All tumor measurements must be recorded in millimeters (or decimal fractions of 
centimeters). 
Malignant lymph nodes: to be considered pathologically enlarged and measurable, a lymph 
node must be  15 mm in short axis when assessed by CT scan (CT scan slice thickness 
recommended to be not greater than 5 mm). At baseline and in follow-up, only the short axis 
will be measured and followed.  
Nonmeasurable 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), as well as truly nonmeasurable 
lesions, are considered nonmeasurable disease. Lesions considered truly nonmeasurable 
include leptomeningeal disease, ascites, pleural/pericardial effusions, inflammatory breast 
disease, lymphangitic involvement of skin and lung, and abdominal masses/abdominal 
organomegaly identified by physical exam that is not measurable by reproducible imaging 
techniques.  
Bone Lesions 
Bone lesions, cystic lesion, and lesions previously treated with local therapy require 
particular comment. Bone scan, PET scan, or plain films are not considered adequate 
imaging techniques to measure bone lesions. However, these techniques can be used to 
confirm the presence or disappearance of bone lesions. 
Lytic bone lesions or mixed lytic–blastic lesions with identifiable soft tissue components that 
can be evaluated by cross-sectional imaging techniques such as CT or MRI can be considered 
as measurable lesions if the soft tissue component meets the definition of measurability 
described above. 
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Blastic bone lesions are nonmeasurable. 
Cystic Lesions 
Lesions that meet the criteria for radiographically defined simple cysts should not be 
considered as malignant lesions (neither measurable nor nonmeasurable) because 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 noncystic lesions 
are present in the same patient, these are preferred as target lesions. 
Lesions with Prior Local Treatment 
Tumor lesions situated in a previous irradiated area or in an area subjected to other 
locoregional therapy are usually not considered measurable unless there has been 
demonstrated progression in the lesion. 
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) and their suitability for accurate repeated measurements (either by 
imaging techniques or clinically). A sum of the longest diameter (LD) for all target lesions 
will be calculated and reported as the baseline sum LD. The baseline sum LD will be used as 
reference by which to characterize the objective tumor response.  
Nontarget Lesions 
RECIST criteria require unequivocal quantification of the changes in tumor size for adequate 
interpretation of the sum of target lesions. Consequently, when the boundaries of the primary 
are difficult to delineate, this tumor should not be considered a target lesion. 
Guidelines for Evaluation of Measurable Disease 
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 when both methods have been used to assess 
the antitumor effect of a treatment. 
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Evaluation of Target Lesions 
Complete Response 
Disappearance of all target lesions. Any pathological lymph nodes 
(whether target or nontarget) must have reduction in short axis to 
< 10 mm. 
Partial Response 
At least a 30% decrease in the sum of the LD of target lesions, taking 
as reference the baseline sum LD. 
Stable Disease 
Neither sufficient shrinkage to qualify for partial response nor 
sufficient increase to qualify for PD, taking as reference the smallest 
sum LD since the treatment started. 
Progressive Disease 
At least a 20% increase in the sum of the LD 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. The appearance of one or more new lesions is also considered 
progression. 
Abbreviations: LD = longest diameter; PD = progressive disease. 
 
Evaluation of Nontarget Lesions 
Complete Response 
Disappearance of all nontarget lesions and normalization of tumor 
marker level. 
Stable Disease/Incomplete 
Response 
Persistence of 1 or more nontarget lesion(s) or/and maintenance of 
tumor marker level above the normal limits. 
Progressive Disease 
Appearance of 1 or more new lesions and/or unequivocal 
progression of existing nontarget lesions. 
If tumor markers are initially above the institutional ULN, they must normalize for a patient 
to be considered a complete responder.  
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 PD 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.  
Evaluation of Best Overall Response 
Target Lesions 
Nontarget Lesions 
New Lesions 
Overall Response 
CR 
CR 
No 
CR 
CR 
Non-CR/non-PD 
No 
PR 
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Evaluation of Best Overall Response 
Target Lesions 
Nontarget Lesions 
New Lesions 
Overall Response 
CR 
Not evaluated 
No 
PR 
PR 
Non-PD or not 
evaluated 
No 
PR 
SD 
Non-PD or not 
evaluated 
No 
SD 
Not Evaluated 
Non-PD 
No 
NE 
PD 
Any 
Yes or No 
PD 
Any 
PD 
Yes or No 
PD 
Any 
Any 
Yes 
PD 
CR 
= 
complete response 
NE 
= 
not evaluable. 
PD 
= 
progressive disease 
PR 
= 
partial response 
SD 
= 
stable disease 
Patients with a global deterioration of health status requiring discontinuation of treatment 
without objective evidence of disease progression at that time should be classified as having 
symptomatic deterioration. Every effort should be made to document the objective 
progression, even after discontinuation of treatment. 
In some circumstances, it may be difficult to distinguish residual disease from normal tissue. 
When the evaluation of CR depends on this determination, it is recommended that the 
residual lesion be investigated (fine needle aspiration/biopsy) prior to confirming the 
complete response status. 
Confirmatory Measurement/Duration of Response 
Confirmation 
If a complete response (CR) or partial response (PR) is noted, confirmatory scans should be 
performed at least 4 weeks after response was first documented. 
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 PD is objectively 
documented (taking as reference for PD the smallest measurements recorded since the 
treatment started). 
The duration of overall CR is measured from the time measurement criteria are first met for 
CR until the first date that recurrent disease is objectively documented. 
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Duration of Stable Disease 
Stable disease (SD) 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. 
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STATISTICAL ANALYSIS PLAN 
SEASTAR: A Phase 1b/2, Open-label, Parallel Arm Study to Assess the 
Safety, Tolerability, Pharmacokinetics, and Preliminary Efficacy of Oral 
Rucaparib in Combination with Other Anticancer Agents in Patients with a 
Solid Tumor 
Arm B: rucaparib and IMMU-132 (sacituzumab govitecan) 
PROTOCOL NUMBER: 
CO-338-098 
VERSION: 
1.0 
DATE FINAL: 
 01 March 2021 
SPONSOR: 
Clovis Oncology, Inc. 
 
 
CONFIDENTIAL 
The information contained in this document is regarded as confidential 
and, except to the extent necessary to obtain informed consent, may not be 
disclosed to another party unless such disclosure is required by law or 
regulations. Persons to whom the information is disclosed must be 
informed that the information is confidential and may not be further 
disclosed by them. 
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Approval Page 
 
 
 
Statistician 
 
 
 
 
 
 
 
 
 
Signature/Date 
 
 
 
 
 
 
  
 
 
Printed Name 
 
 
 
 
  
  
Clinical Development 
  
 
 
 
  
 
 
Signature/Date 
  
 
 
 
 
  
 
 
Printed Name 
 
 
 
 
  
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TABLE OF CONTENTS 
TABLE OF CONTENTS ...........................................................................................................3 
LIST OF IN-TEXT TABLES ....................................................................................................4 
LIST OF APPENDICES ............................................................................................................4 
ABBREVIATIONS AND SPECIALIST TERMS ....................................................................5 
1 
INTRODUCTION ...........................................................................................................6 
2 
OVERALL STUDY DESIGN, OBJECTIVES, AND ENDPOINTS .............................6 
2.1 
Study Design ............................................................................................................6 
2.2 
Study Objectives and Endpoints ..............................................................................7 
2.3 Sample Size Justification ...............................................................................................8 
3 
GENERAL ANALYSIS CONVENTIONS ....................................................................8 
3.1 
Analysis Populations ................................................................................................8 
4 
PATIENT DISPOSITION ...............................................................................................8 
5 
PROTOCOL DEVIATIONS ...........................................................................................9 
6 
DEMOGRAPHICS AND BASELINE CHARACTERISTICS ......................................9 
6.1 
Demographics ..........................................................................................................9 
6.2 
Baseline Clinical Characteristics .............................................................................9 
6.3 
Medical History .......................................................................................................9 
7 
DOSE-LIMITING TOXICITIES ....................................................................................9 
8 
STUDY DRUG EXPOSURE AND COMPLIANCE ...................................................10 
9 
PRIOR AND CONCOMITANT MEDICATIONS ......................................................10 
10 
EFFICACY ANALYSIS ...............................................................................................10 
11 
EXPLORATORY ANALYSIS .....................................................................................11 
12 
PHARMACOKINETIC ANALYSIS ...........................................................................11 
13 
SAFETY ANALYSIS ...................................................................................................11 
13.1 
Adverse Events ......................................................................................................11 
13.2 
Clinical Laboratory Evaluations ............................................................................12 
13.3 
Vital Signs ..............................................................................................................12 
14 
STATISTICAL / ANALYTICAL ISSUES ..................................................................12 
14.1 
Handling of Dropouts or Missing Data ..................................................................12 
14.2 
Pooling of Centers in Multi-Center Studies ...........................................................12 
14.3 
Multiple Comparison / Multiplicity .......................................................................12 
14.4 
Examination of Subgroups .....................................................................................12 
14.5 
Interim Analyses and Data Monitoring..................................................................13 
15 
REFERENCES ..............................................................................................................14 
16 
APPENDICES ...............................................................................................................15 
 
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LIST OF IN-TEXT TABLES 
Table 1.  
Primary, Secondary, and Exploratory Objectives and Endpoints………………………...7 
LIST OF APPENDICES 
Appendix 1 Response Evaluation Criteria in Solid Tumors………………………………………..….15 
 
 
 
 
 
 
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ABBREVIATIONS AND SPECIALIST TERMS 
AE(s) 
adverse event(s) 
ANC 
absolute neutrophil count 
AST 
aspartate aminotransferase 
ALT 
alanine aminotransferase 
BID 
twice daily 
CEOI 
concentration at the end of infusion 
Cmin 
 minimum concentration 
CRM 
cohort review meeting 
CR 
complete response 
CSR 
clinical study report 
CTCAE 
Common Terminology Criteria for Adverse Events 
ctDNA 
circulating cell-free tumor DNA 
DLT 
dose limiting toxicity 
ECG 
electrocardiogram 
GCSF 
granulocyte colony-stimulating factor 
IMMU-132 
sacituzumab govitecan 
MTD 
 maximum tolerated dose 
NCI 
National Cancer Institute 
ORR 
objective response per RECIST 
PD 
progressive disease 
PK 
pharmacokinetic(s) 
PR 
partial response 
RP2D 
Recommended Phase 2 dose 
RECIST 
Response Evaluation Criteria in Solid Tumors 
SAE 
serious adverse event 
SAP  
statistical analysis plan 
SD 
stable disease 
SI 
International System of Units 
StD 
standard deviation 
TEAE 
treatment-emergent adverse event 
ULN 
upper limit of normal 
 
 
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1 INTRODUCTION 
This statistical analysis plan (SAP) describes the data summaries and any statistical analyses 
to be performed to assess the safety, efficacy, and pharmacokinetics (PK) of rucaparib (CO-
338) for Clovis Oncology, Inc sponsored clinical study CO-338-098, entitled “SEASTAR: A 
Phase 1b/2, Open-label, Parallel Arm Study to Assess the Safety, Tolerability, 
Pharmacokinetics, and Preliminary Efficacy of Oral Rucaparib in Combination with Other 
Anticancer Agents in Patients with a Solid Tumor.” This SAP addresses the Phase 1b portion 
of Arm B of the study since the study did not continue to Phase 2. Enrollment in Arm B, 
Phase 1b was halted after 2 dose cohorts, so the analysis plan will be reduced from what was 
indicated in the protocol in order to support a synoptic clinical study report (CSR). It is 
anticipated that results for Arm A, which is still ongoing at this time, will be analyzed under 
a different SAP.  
2 OVERALL STUDY DESIGN, OBJECTIVES, AND ENDPOINTS 
2.1 STUDY DESIGN 
For the Phase 1b portion of Arm B, the plan estimated 6 to 12 dose-escalation cohorts, with a 
minimum of 3 patients enrolled in each cohort, followed by an expanded evaluation of the 
recommended phase 2 dose (RP2D) in up to 10 additional patients. Dose escalation was to 
follow a 3+3 design.  
 
The initial combination dose consists of oral rucaparib 300 mg twice daily (BID), 
administered continuously, in combination with IV IMMU-132 6 mg/kg administration on 
Day 1 and Day 8 of a 21-day cycle. The dose of rucaparib was to be escalated in 100 mg BID 
increments up to a maximum of 600 mg BID. The dose of IMMU-132 was to be escalated in 
increments of 2 mg/kg, up to a maximum dose of 10 mg/kg. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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2.2 STUDY OBJECTIVES AND ENDPOINTS 
Because this study was halted before phase 1b was complete, not all endpoints from the 
protocol will be analyzed. Table 1 outlines the objectives and endpoints planned per protocol 
for Phase 1b of Arm B. The final column includes the analyses to be included in the CSR. 
Table 1. 
Primary, Secondary, and Exploratory Objectives and Endpoints for 
Phase 1b 
Primary Objectives 
Primary Endpoints 
Included in CSR 
To evaluate the safety and tolerability of 
rucaparib in combination with IMMU-132 
and to determine the maximum tolerated dose 
(MTD) and/or the RP2D of the combination. 
Incidence of AEs, clinical 
laboratory abnormalities, dose 
modifications, and listings of ECGs 
and vital signs  
AEs, some clinical 
laboratories, and 
dose modifications 
will be included 
Secondary Objectives 
Secondary Endpoints 
 
To characterize the PK of IMMU-132 and its 
metabolites when rucaparib and IMMU-132 
agent are co-administered. 
Plasma concentration at trough 
(Cmin) and at the end of infusion 
(CEOI) 
Not included in 
CSR 
To evaluate the preliminary efficacy of 
rucaparib in combination with IMMU-132 in 
various solid tumors. 
Objective response per RECIST 
v1.1 (ORR) 
Included in the 
CSR 
Exploratory Objectives 
Exploratory Endpoints 
 
To assess tumor tissue biomarkers that 
correlate with response to the combination. 
Not defined in protocol 
Not included in 
CSR 
To evaluate circulating cell-free tumor DNA 
(ctDNA) as a molecular marker of response 
to the combination. 
Not defined in protocol 
Not included in 
CSR 
To evaluate biomarkers associated with 
resistance to the combination. 
Not defined in protocol 
Not included in 
CSR 
To assess genomic changes over time in 
plasma and tumor samples. 
Not defined in protocol 
Not included in 
CSR 
To determine steady-state exposure of 
rucaparib by sparse PK sampling. 
Not defined in protocol 
Not included in 
CSR 
To evaluate the development of anti-drug 
antibodies (ADAs). 
Not defined in protocol 
Not included in 
CSR 
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2.3 SAMPLE SIZE JUSTIFICATION 
For Arm B Phase 1b, it was estimated that up to 55 patients would be enrolled following a 
standard 3+3 design, dependent upon the occurrence of safety findings, specifically DLTs, 
observed at the different dose levels. 6 subjects were enrolled before the study was halted. 
3  GENERAL ANALYSIS CONVENTIONS 
Quantitative variables will typically be summarized using frequencies and percentages for 
appropriate categorizations and may also be summarized using descriptive statistics. For 
variables summarized with descriptive statistics, the following will be presented: N, mean, 
standard deviation (StD), median, minimum, and maximum. Categorical variables will be 
presented using frequencies and percentages.  
Baseline is defined as the last measurement on or prior to the first dose of rucaparib 
administration, unless otherwise specified.  
All statistical analyses will be conducted with the SAS® System, Version 9.4 or higher.  
3.1 ANALYSIS POPULATIONS 
The following analysis populations are defined for the study: 
Safety Population: All patients who have received at least 1 dose of rucaparib or IMMU-
132.  
 
DLT-evaluable Population: All patients in Phase 1b who have either received at least 80% 
of the planned doses of rucaparib and both planned infusions of IMMU-132 without having 
experienced a DLT or who experienced a DLT during Cycle 1. If a patient withdrew from the 
study without having met any of these criteria, then an additional patient was enrolled in that 
dose cohort. 
 
Efficacy Population: All patients who have received at least 1 dose of rucaparib or IMMU-
132 and who have measurable disease per RECIST v1.1 at baseline. 
4 PATIENT DISPOSITION 
Patient disposition will be summarized using frequency counts and the corresponding 
percentages. The number of patients in each analysis population, number of patients 
discontinued, and the primary reason for treatment discontinuation will be summarized.
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5 PROTOCOL DEVIATIONS 
Protocol deviations will not be analyzed in Arm B of the SEASTAR study. 
6 DEMOGRAPHICS AND BASELINE CHARACTERISTICS 
All demographic will be summarized for the safety population. 
6.1 DEMOGRAPHICS 
The demographic variables will be summarized with frequency tabulations and descriptive 
statistics. The demographic variables presented will include age, height, weight and sex using 
the following categorizations: 
• Age (years): ≤ 50, 51-60, 61-70, 71-80, 81-90, > 90; 
• Height (cm): ≤ 75, > 75-100, > 100-125, > 125-150, > 150-175, > 175; 
• Weight (kg): ≤ 50, > 50-75, > 75-100, > 100-125, > 125-150, > 150 
• Sex: Male, Female 
6.2 BASELINE CLINICAL CHARACTERISTICS 
No baseline disease characteristics will be analyzed in the CSR. 
6.3 MEDICAL HISTORY 
In a change from the protocol, medical history events will not be analyzed. 
7 DOSE-LIMITING TOXICITIES 
A summary of the number of DLTs by dose level and a patient listing of all DLTs will be 
provided for the patients in the DLT-evaluable population. A DLT is defined at any of the 
following events occurring in Cycle 1, according to CTCAE version 5.0: 
 Grade 3 or greater febrile neutropenia (i.e., fever > 38.3°C with Absolute Neutrophil 
Count (ANC) < 1.0 × 109/L) of any duration; 
 Grade 3 or 4 neutropenia lasting more than 7 days despite granulocyte colony-
stimulating factor (GCSF) administration; Grade 3 thrombocytopenia (platelets < 50 
× 109/L) with significant bleeding or Grade 4 thrombocytopenia (platelets < 25 × 
109/L) ≥ 5 days duration; 
 Grade 4 anemia (i.e., life-threatening consequences; urgent intervention indicated) or 
any anemia (regardless of grade or severity) requiring a blood transfusion;  
 Any nonhematological AE ≥ Grade 3, with the exception of: 
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o Nausea, vomiting, and diarrhea if well controlled by systemic medication and 
with duration ≤ 48 hrs; 
o Fatigue; 
o Grade 3 alanine aminotransferase (ALT) or aspartate aminotransferase (AST) 
not accompanied by a concomitant increase in total bilirubin above the upper 
limit of normal (ULN). Note: any Grade 4 ALT/AST is a DLT. 
 Any Grade 3 or greater infusion-related reaction that fails to resolve within 4 hours 
despite optimal medical management. 
8 STUDY DRUG EXPOSURE AND COMPLIANCE 
The following variables will be summarized: 
 Duration of treatment (days) 
 Number of dose reductions 
 Number of dose interruptions 
Duration of treatment will be calculated as 1+ the number of days from earliest study drug 
start date to date of last study drug discontinuation. Descriptive statistics and 
frequencies/percentages for appropriate categorizations will be used to summarize study drug 
exposure variables. 
9 PRIOR AND CONCOMITANT MEDICATIONS 
Prior and concomitant medications will not be analyzed in the CSR.  
10  EFFICACY ANALYSIS 
Efficacy analyses will be performed using the efficacy population. 
Overall objective response to treatment according to RECIST v1.1 as assessed by the 
investigator will be listed along with target lesion measurements and response, non-target 
lesion response, and assessment of new lesions. Confirmation of a complete response (CR) or 
partial response (PR) is a response that is maintained and documented on a subsequent tumor 
assessment no less than 4 weeks after initial response and will be indicated on the listing. 
Duration of response will also be calculated as the time from the date that a confirmed PR or 
CR is first recorded until the first date that progressive disease (PD) is documented per 
RECIST v1.1. Duration of stable disease (SD) will be calculated from the start of treatment 
to the first PD if the subject had a best response of SD. 
 
A listing of all tumor scan details collected, including ORR, in the clinical database will be 
provided. 
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11  EXPLORATORY ANALYSIS 
No exploratory endpoints will be analyzed in the CSR. 
12  PHARMACOKINETIC ANALYSIS 
PK analyses, including the secondary endpoint, will no longer be included in the CSR due to 
the early termination of the study.  
13 SAFETY ANALYSIS 
The safety analyses will be performed using the safety population. 
13.1  ADVERSE EVENTS 
Adverse events (AEs) will be classified using the MedDRA classification system. The 
severity of the toxicities will be graded according to the National Cancer Institute (NCI) 
Common Terminology Criteria for Adverse Events (CTCAE) v5.0 whenever possible. 
Treatment-emergent adverse events (TEAEs) are defined as AEs with onset date on or after 
the date of first dose of study medication until the date of the last study medication dose plus 
28 days. Adverse events will be considered treatment-emergent if all or part of the date of 
onset of the AE is missing and it cannot be determined if the AE meets the definition for 
treatment-emergent. 
The number and percentage of patients who experienced TEAEs for each system organ class 
and preferred term will be presented. Multiple instances of the TEAE in each system organ 
class and multiple occurrences of the same preferred term are counted only once per patient. 
The number and percentage of patients with at least one TEAE will also be summarized.   
The incidence of TEAEs will also be summarized by relationship to study drug according to 
the following categories: “treatment-related,” or “not treatment-related” for each study drug. 
If a patient experiences multiple occurrences of the same AE with different relationship 
categories, the patient will be counted once, as a relationship category of treatment-related.   
If a patient experiences multiple occurrences of the same AE with different toxicity grades, 
the patient will be counted once for the maximum (most severe) toxicity grade. AEs with a 
missing toxicity grade will be presented in the summary table with a toxicity grade of 
“Missing.” For each toxicity grade, the number and percentage of patients with at least one 
TEAE of the given grade will be summarized.    
Separate tables will be presented including but not limited to: 
• All TEAEs; 
• TEAEs by CTCAE grade; 
• Grade 3 or greater TEAEs; 
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• Treatment-related TEAEs, overall and by categories: CTCAE grade, grade 3 or greater, 
resulting in dose reduction, resulting in dose interruption, resulting in dose 
discontinuation, outcome of death; 
• Serious TEAEs; 
• TEAEs with an outcome of death; 
• TEAEs leading to discontinuation of study medication; 
• TEAEs resulting in interruption of study medication; and 
• TEAEs resulting in reduction, delay, or interruption of study medication. 
13.2 CLINICAL LABORATORY EVALUATIONS 
Clinical laboratory evaluations include the continuous variables for hematology, chemistry, 
and urinalysis. The laboratory values will generally be presented in International System (SI) 
units. The on-treatment period will be defined as the time from earliest first dose to 28 days 
after the last dose of rucaparib or IMMU-132, whichever is last. Hematology values collected 
will be listed. Descriptive summaries, and all chemistry and urinalysis parameters, mentioned 
in the protocol will not be included in the analysis.    
13.3 VITAL SIGNS 
Vital signs will not be analyzed in this study. 
14  STATISTICAL / ANALYTICAL ISSUES 
14.1  HANDLING OF DROPOUTS OR MISSING DATA 
All data will be used to their maximum possible extent, but without any imputations for 
missing data.  
14.2  POOLING OF CENTERS IN MULTI-CENTER STUDIES 
All centers will be pooled for analysis. 
14.3  MULTIPLE COMPARISON / MULTIPLICITY 
No statistical comparisons will be performed. 
14.4  EXAMINATION OF SUBGROUPS 
Analyses of primary and secondary endpoints may be analyzed by starting dose. No 
additional subgroup analyses will be performed. 
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14.5  INTERIM ANALYSES AND DATA MONITORING 
No formal interim analyses were planned outside standard Cohort Review Meetings (CRM). 
CRMs were held for the first 2 dose cohorts and the decision was made to forgo exploration 
of any other dose cohorts.  
 
 
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15  REFERENCES 
1. Eisenhauer EA, Therasse P, Bogaerts J, Schwartz LH, Sargent D, Ford R, et al. New response 
evaluation criteria in solid tumours: revised RECIST guideline (version 1.1). Eur J Cancer. 
2009;45(2):228-47. 
 
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16 APPENDICES 
Appendix 1 
Response Evaluation Criteria in Solid Tumors 
The RECIST guidelines (Version 1.1) are described in Eisenhauer (2009)1 and at 
http://www.eortc.be/Recist/Default.htm. A short summary is given below. 
Measurable Disease: 
Tumor lesions: measurable lesions are defined as those that can be accurately measured in at 
least 1 dimension (longest diameter to be recorded) with the following: 
 A minimum size of 10 mm by CT scan (CT scan thickness no greater than 5 mm). 
 A minimum size of 10 mm caliper measurement by clinical exam (lesions that cannot be 
accurately measured with calipers should be recorded as nonmeasurable). 
 A minimum size of 20 mm by chest X-ray. 
All tumor measurements must be recorded in millimeters (or decimal fractions of 
centimeters). 
Malignant lymph nodes: to be considered pathologically enlarged and measurable, a lymph 
node must be  15 mm in short axis when assessed by CT scan (CT scan slice thickness 
recommended to be not greater than 5 mm). At baseline and in follow-up, only the short axis 
will be measured and followed.  
Nonmeasurable 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), as well as truly nonmeasurable 
lesions, are considered nonmeasurable disease. Lesions considered truly nonmeasurable 
include leptomeningeal disease, ascites, pleural/pericardial effusions, inflammatory breast 
disease, lymphangitic involvement of skin and lung, and abdominal masses/abdominal 
organomegaly identified by physical exam that is not measurable by reproducible imaging 
techniques.  
Bone Lesions 
Bone lesions, cystic lesion, and lesions previously treated with local therapy require 
particular comment. Bone scan, PET scan, or plain films are not considered adequate 
imaging techniques to measure bone lesions. However, these techniques can be used to 
confirm the presence or disappearance of bone lesions. 
Lytic bone lesions or mixed lytic–blastic lesions with identifiable soft tissue components that 
can be evaluated by cross-sectional imaging techniques such as CT or MRI can be considered 
as measurable lesions if the soft tissue component meets the definition of measurability 
described above. 
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Blastic bone lesions are nonmeasurable. 
Cystic Lesions 
Lesions that meet the criteria for radiographically defined simple cysts should not be 
considered as malignant lesions (neither measurable nor nonmeasurable) because 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 noncystic lesions 
are present in the same patient, these are preferred as target lesions. 
Lesions with Prior Local Treatment 
Tumor lesions situated in a previous irradiated area or in an area subjected to other 
locoregional therapy are usually not considered measurable unless there has been 
demonstrated progression in the lesion. 
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) and their suitability for accurate repeated measurements (either by 
imaging techniques or clinically). A sum of the longest diameter (LD) for all target lesions 
will be calculated and reported as the baseline sum LD. The baseline sum LD will be used as 
reference by which to characterize the objective tumor response.  
Nontarget Lesions 
RECIST criteria require unequivocal quantification of the changes in tumor size for adequate 
interpretation of the sum of target lesions. Consequently, when the boundaries of the primary 
are difficult to delineate, this tumor should not be considered a target lesion. 
Guidelines for Evaluation of Measurable Disease 
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 when both methods have been used to assess 
the antitumor effect of a treatment. 
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Evaluation of Target Lesions 
Complete Response 
Disappearance of all target lesions. Any pathological lymph nodes 
(whether target or nontarget) must have reduction in short axis to 
< 10 mm. 
Partial Response 
At least a 30% decrease in the sum of the LD of target lesions, taking 
as reference the baseline sum LD. 
Stable Disease 
Neither sufficient shrinkage to qualify for partial response nor 
sufficient increase to qualify for PD, taking as reference the smallest 
sum LD since the treatment started. 
Progressive Disease 
At least a 20% increase in the sum of the LD 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. The appearance of one or more new lesions is also considered 
progression. 
Abbreviations: LD = longest diameter; PD = progressive disease. 
 
Evaluation of Nontarget Lesions 
Complete Response 
Disappearance of all nontarget lesions and normalization of tumor 
marker level. 
Stable Disease/Incomplete 
Response 
Persistence of 1 or more nontarget lesion(s) or/and maintenance of 
tumor marker level above the normal limits. 
Progressive Disease 
Appearance of 1 or more new lesions and/or unequivocal 
progression of existing nontarget lesions. 
If tumor markers are initially above the institutional ULN, they must normalize for a patient 
to be considered a complete responder.  
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 PD 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.  
Evaluation of Best Overall Response 
Target Lesions 
Nontarget Lesions 
New Lesions 
Overall Response 
CR 
CR 
No 
CR 
CR 
Non-CR/non-PD 
No 
PR 
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Evaluation of Best Overall Response 
Target Lesions 
Nontarget Lesions 
New Lesions 
Overall Response 
CR 
Not evaluated 
No 
PR 
PR 
Non-PD or not 
evaluated 
No 
PR 
SD 
Non-PD or not 
evaluated 
No 
SD 
Not Evaluated 
Non-PD 
No 
NE 
PD 
Any 
Yes or No 
PD 
Any 
PD 
Yes or No 
PD 
Any 
Any 
Yes 
PD 
CR 
= 
complete response 
NE 
= 
not evaluable. 
PD 
= 
progressive disease 
PR 
= 
partial response 
SD 
= 
stable disease 
Patients with a global deterioration of health status requiring discontinuation of treatment 
without objective evidence of disease progression at that time should be classified as having 
symptomatic deterioration. Every effort should be made to document the objective 
progression, even after discontinuation of treatment. 
In some circumstances, it may be difficult to distinguish residual disease from normal tissue. 
When the evaluation of CR depends on this determination, it is recommended that the 
residual lesion be investigated (fine needle aspiration/biopsy) prior to confirming the 
complete response status. 
Confirmatory Measurement/Duration of Response 
Confirmation 
If a complete response (CR) or partial response (PR) is noted, confirmatory scans should be 
performed at least 4 weeks after response was first documented. 
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 PD is objectively 
documented (taking as reference for PD the smallest measurements recorded since the 
treatment started). 
The duration of overall CR is measured from the time measurement criteria are first met for 
CR until the first date that recurrent disease is objectively documented. 
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Duration of Stable Disease 
Stable disease (SD) 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. 
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