Clinical trial NCT03644342
Conditions: Metastatic Carcinoma of the Cervix
Keywords: cervical cancer Niraparib radiotherapy carcinoma of the cervix
Sponsor: Michelle S Ludwig
Start date: 2019-07-15; Completion date: 2023-09-27
Enrollment: 4 participants; Allocation: NON_RANDOMIZED; Intervention model: SEQUENTIAL

Brief summary:
The most effective strategy for managing distantly metastatic invasive carcinomas of the cervix is not defined. Based on the success of niraparib in breast and ovarian cancer trials and the concern for toxicities and comorbidities limiting the compliance of concurrent cisplatin for cervical cancer, this study is a phase I/II study of women diagnosed with distantly metastatic (Stage IV) disease to determine the maximum tolerated dose and to evaluate the safety, tolerability and preliminary efficacy of niraparib, an orally available small molecule PARP inhibitor when administered concurrently with definitive regional radiotherapy for treatment of cervical cancer. Women enrolled in this study will receive 3-6 cycles of induction-style carboplatin and paclitaxel followed by definitive doses of pelvic radiotherapy along with the oral niraparib given at the same time.

Detailed description:

Arms: arm 1: For the purposes of this study, two dose levels of Niraparib (100 mg will be evaluated concomitant with the concurrent administration of pelvic radiotherapy. arm 2: For the purposes of this study, two dose levels of Niraparib (200 mg) will be evaluated concomitant with the concurrent administration of pelvic radiotherapy.
Interventions: intervention 1: Nirapaib
Intervention descriptions: intervention 1: (see treatment regimen and method of treatment assignment)

Protocol documents:
Prot_SAP_000.pdf: 
NIRAPARIB  
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Phase I/II Study of Niraparib with Radiotherapy for 
Treatment of Metastatic Invasive Carcinoma of the Cervix 
(NIVIX) 
Sponsor: Baylor College of Medicine 
Principal Investigator: Michelle S. Ludwig, MD, MPH, PhD 
Sponsor Protocol Number: H-40404 
Study Drug Name: Niraparib  
Clinical Phase:  I/II 
Number of Subjects: 24 
IND Number: 137,284 
EudraCT Number: N/A 
Date of Original Protocol: 5/31/2017 
Date of Current Protocol: 12/4/2019 
Version:     5.0 
 
The study will be conducted according to the protocol and in compliance with Good Clinical Practice 
(GCP), with the Declaration of Helsinki, and with other applicable regulatory requirements including 
but not limited to Institutional Review Board/Ethics Committee (IRB/EC) approval. 
 
Confidentiality Statement 
All information contained in this document is privileged and confidential. Any distribution, 
copying, or disclosure is strictly prohibited without prior written approval by the Sponsor. 
 
 


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LIST OF STUDY CONTACTS  
 
Sponsor 
Michelle S. Ludwig 
Department of  
Radiation Oncology 
Baylor College of Medicine 
One Baylor Plaza, BCM711 
Houston, TX 77030 
Cell: 713-724-4440 (c) 
Email: 
Michelle.Ludwig@bcm.edu  
 
Principal Investigator 
Michelle S. Ludwig 
Department of Radiation Oncology 
Baylor College of Medicine 
One Baylor Plaza, BCM711 
Houston, TX 77030 
Cell: 713-724-4440 (c) 
Email: Michelle.Ludwig@bcm.edu  
 
Co- Principal Investigator 
Matthew Anderson, MD, PhD 
Department of Obstetrics and 
Gynecology 
USF Morsani College of 
Medicine 
12901 Bruce B. Downs Blvd, 
MDC2041 
Tampa, FL 33612 
Phone: 813-974-1806 
Email: 
mlander5@health.usf.edu  
Co-Investigator 
Tracilyn Hall, MD 
Co-Investigator 
Alfredo Echeverria, MD 
Department of Radiation Oncology 
Baylor College of Medicine 
One Baylor Plaza, BCM711 
Houston, TX 77030 
Phone: 713-566-3757 
Email: echeverr@bcm.edu 
 
Co-Investigator 
Pavan Jhaveri, MD 
Department of Radiation Oncology 
Baylor College of Medicine 
One Baylor Plaza, BCM711 


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Department of 
Gynecologic 
Oncology 
Baylor College of Medicine 
6654 Main Street, Suite 1050 
Houston, TX 77030 
Phone: 832-826-7486 
Email: Tracilyn.Hall@bcm.edu  
Co-Investigator 
Jan Sunde, MD 
Department of 
Gynecologic 
Oncology 
Baylor College of Medicine 
6654 Main Street, Suite 1050 
Houston, TX 77030 
Phone: 832-826-7486 
Email: Jan.Sunde@bcm.edu  
Study Statistician 
Anna Frolov 
Biostatistics Program 
Dan L. Duncan 
Comprehensive Cancer 
Center 
Baylor College of Medicine 
One Baylor Plaza, BCM305 
Phone: 713-798-8802 
Email:  afrolov@bcm.edu  
 
 
Houston, TX 77030 
Phone: 713-566-3757 
Email: Pavan.Jhaveri@bcm.edu 
Co-Investigator 
Anthony Costales, MD 
Department of Gynecologic Oncology 
Baylor College of Medicine 
6654 Main Street, Suite 1050 
Houston, TX 77030 
Phone: 832-826-7486 
Email: costales@bcm.edu 
Co-Investigator 
Claire Hoppenot, MD 
Department of Gynecologic Oncology 
Baylor College of Medicine 
6654 Main Street, Suite 1050 
Houston, TX 77030 
Phone: 832-826-7486 
Email:  Claire.Hoppenot@bcm.edu  
 


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Study Coordinating Group 
Clinical Trials Support Unit 
Dan L Duncan Comprehensive 
Cancer Center 
Baylor College of Medicine 
One Baylor Plaza, Suite 450A 
Houston, TX 77030 
Phone: 713-798-1354 
Email: ctsu-dldcc@bcm.edu  
 
 
 


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SPONSOR SIGNATURE PAGE 
 
Declaration of Sponsor or Responsible Medical Officer 
 
Title: Phase I/II Study of Niraparib with Radiotherapy for Treatment of 
Metastatic Invasive Carcinoma of the Cervix (NIVIX) 
Version Date:   December 4, 2019 
 
This study protocol was subjected to critical review and has been approved by the 
Sponsor. The information it contains is consistent with the current risk/benefit 
evaluation of the investigational product as well as with the moral, ethical, and 
scientific principles governing clinical research as set out in the Declaration of 
Helsinki and the guidelines on Good Clinical Practice. 
 
Sponsor 
 
 
_____________________________________ _____________________ 
[Michelle S. Ludwig] 
Date  
[MD, PhD, MPH] 
[Baylor College of Medicine] 


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INVESTIGATOR SIGNATURE PAGE 
Declaration of the Investigator 
 
Title: Phase I/II Study of Niraparib with Radiotherapy for Treatment of 
Metastatic Invasive Carcinoma of the Cervix (NIVIX) 
Version Date:  December 4, 2019 
I have read this study protocol, including all appendices.  By signing this protocol, 
I agree to conduct the clinical study, following approval by an Independent Ethics 
Committee (IEC)/Institutional Review Board (IRB), in accordance with the study 
protocol, the current International Conference on Harmonisation (ICH) Guideline for 
Good Clinical Practice (GCP), and applicable regulatory requirements.  I will ensure 
that all personnel involved in the study under my direction will be informed about the 
contents of this study protocol and will receive all necessary instructions for 
performing the study according to the study protocol. 
 
Investigator 
 
 
_____________________________________ _____________________ 
[Michelle S. Ludwig] 
Date 
[MD, MPH, PhD]   
[Baylor College of Medicine]   
 
 


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TABLE OF CONTENTS 
SPONSOR SIGNATURE PAGE ................................................................................ 5 
Investigator Signature Page .................................................................................... 6 
List of Abbreviations and Definitions .................................................................. 10 
1 
Introduction ................................................................................................. 12 
 
Study Design ......................................................................................... 12 
 
Primary Objective .................................................................................. 13 
 
Secondary Objectives ........................................................................... 13 
 
Correlative Objectives ........................................................................... 13 
2 
Background and significance .................................................................... 14 
 
Background of PARP and Homologous Recombination Deficiency ...... 14 
 
Background of Niraparib ....................................................................... 15 
2.2.1 
Non-clinical Experience ................................................................... 15 
2.2.2 
Clinical Experience .......................................................................... 16 
 
Rationale for Current Study ................................................................... 19 
2.3.1 
Rationale for Study Population ........................................................ 19 
2.3.2 
Rationale for Objectives ................................................................... 20 
2.3.3 
Rationale for Measures .................................................................... 20 
3 
Participant selection ................................................................................... 22 
3.1 Inclusion Criteria ............................................................................................. 22 
 
Exclusion Criteria .................................................................................. 23 
4 
Treatment Plan ............................................................................................ 25 
 
Method of Treatment Assignment ......................................................... 25 
 
Treatment Regimen .............................................................................. 26 
4.2.1 
Other Agent Administration .............................................................. 26 
 
Prohibited Therapies ............................................................................. 27 
 
Birth Control .......................................................................................... 27 
 
Breast Feeding ...................................................................................... 28 
 
Blood Donation ...................................................................................... 28 
 
Dose Escalation .................................................................................... 28 
 
Dose-Limiting Toxicity (DLT) ................................................................. 28 
 
Treatment Discontinuation .................................................................... 29 
 
Duration of Follow Up ............................................................................ 29 
 
Discontinuation from Study ................................................................... 29 
 
Participant Replacement Criteria ........................................................... 30 
5 
Dose Modifications ..................................................................................... 31 
 
Niraparib................................................................................................ 31 


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6 
Pharmaceutical Information ....................................................................... 34 
 
Niraparib................................................................................................ 34 
6.1.1 
Identity ............................................................................................. 34 
6.1.2 
Potential Risks of Niraparib .............................................................. 34 
6.1.3 
Packaging, Labeling and Storage .................................................... 34 
6.1.4 
Drug Accountability .......................................................................... 34 
6.1.5 
Disposal and Destruction ................................................................. 35 
 
Other Agent ........................................................................................... 35 
7 
Correlative Studies...................................................................................... 36 
 
Pharmacodynamics (PARP Testing) ..................................................... 36 
8 
Schedule of Assessments .......................................................................... 38 
 
Screening .............................................................................................. 38 
 
During Radiation (Niraparib given continuously) ................................... 38 
 
Maintenance Therapy (after completion of radiation) ............................ 39 
 
End of Treatment .................................................................................. 39 
 
Follow-up............................................................................................... 40 
 
Long Term Follow-up ............................................................................ 40 
 
Unscheduled Assessments ................................................................... 40 
9 
STUDY CALENDAR ..................................................................................... 42 
10 
Adverse Event Reporting ........................................................................... 46 
 
Definition of Adverse Events ................................................................. 46 
 
Serious Adverse Events (SAEs) ............................................................ 46 
 
Adverse Events of Special Interest ....................................................... 47 
 
Special Situations: Abuse, Misuse, Medication Errors, Overdose, and 
Accidental or Occupational Exposure ................................................................... 47 
 
Reporting Special Situations: ................................................................ 48 
 
Assessment of Adverse Events ............................................................. 48 
10.5.1 
Severity Assessment ....................................................................... 48 
10.5.2 
Relationship to Study Drug .............................................................. 48 
 
Collection and Recording of Adverse Events ........................................ 49 
 
Follow-Up of Adverse Events ................................................................ 50 
 
Reporting to the Sponsor-Investigator ................................................... 50 
 
Reporting to TESARO ........................................................................... 50 
 
Quarterly AE/SAE Reporting to TESARO ............................................. 51 
 
Pregnancy ............................................................................................. 51 
 
Suspected Unexpected Serious Adverse Reactions (SUSARs) ............ 51 
10.12.1 Reporting of SUSARs to the FDA .................................................... 52 
10.12.2 Reporting to IRB .............................................................................. 52 


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Reporting Product Complaints for Niraparib .......................................... 52 
11 
Data reporting .............................................................................................. 53 
 
Data submission .................................................................................... 53 
 
Data and Safety Monitoring ................................................................... 53 
 
Audits .................................................................................................... 53 
 
Data Quality Assurance ........................................................................ 54 
12 
Statistical Methods...................................................................................... 55 
 
Study Design and Endpoints ................................................................. 55 
 
Primary Endpoint ................................................................................... 55 
 
Secondary Endpoints ............................................................................ 55 
 
Sample size, Accrual Rate and Study Duration ..................................... 56 
 
Phase I component considerations. ...................................................... 56 
 
Phase II component considerations. ..................................................... 58 
13 
Ethical, Legal, and Administrative Aspects .............................................. 60 
 
Good Clinical Practice ........................................................................... 60 
 
Informed Consent .................................................................................. 60 
 
Protocol Approval and Amendment ....................................................... 60 
 
Investigator Responsibilities .................................................................. 60 
 
Subject Confidentiality and Data Protection .......................................... 61 
 
Access to Source Documents ............................................................... 61 
 
Archival ................................................................................................. 61 
 
Publications ........................................................................................... 61 
14 
References ................................................................................................... 62 
Appendix 1 – Performance Status ........................................................................ 68 
Appendix 2 –  ResPONSE CRITERIA .................................................................... 69 
Appendix 3: qol form (English) ............................................................................. 71 
Appendix 4: qol form (Spanish) ............................................................................ 75 
Appendix 5 – FIGO staging of cancer of the cervix uteri (2018) ........................ 78 
Appendix 6 – drugs which are inhibitors of p-glycoproteins (from fda drug 
development and drug interactions) .................................................................... 80 
Appendix 7 – Acceptable Chemotherapy Regimens .......................................... 81 


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LIST OF ABBREVIATIONS AND DEFINITIONS 
 
Abbreviation 
Definition 
ADP 
adenosine diphosphate  
AE 
adverse event 
AESI 
adverse event of special interest 
AML 
acute myeloid leukemia 
AUC 
area under the curve 
BER 
base excision repair 
BRCA 
breast cancer gene 
CBC 
complete blood count  
CL 
oral clearance 
CT 
computed tomography  
CTCAE 
Common Terminology Criteria for Adverse Events 
CYP 
cytochrome P450 
DLT 
dose-limiting toxicity 
DNA 
deoxyribonucleic acid 
DDR 
DNA damage repair 
ECOG 
Eastern Cooperative Oncology Group 
EOT 
end of treatment 
FE 
food effect 
gBRCA 
germline breast cancer gene 
GCSF 
Granulocyte-colony stimulating factor 
GBM 
glioblastoma multiforme  
hCG 
human chorionic gonadotropin 
HDR 
High Dose Rate (brachytherapy) 
HR 
homologous recombination 
HRD 
homologous recombination deficiency  
ICRU 
International Commission on Radiation Units 
irAEIs 
immune-related adverse events of interest 
IUD 
intrauterine device 
LDR 
Low Dose Rate (brachytherapy) 
LLN 
Lower limit of normal 
MDS 
myelodysplastic syndrome 
MRI 
magnetic resonance imaging  
MTD 
maximum tolerated dose 


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Abbreviation 
Definition 
NHEJ 
non-homologous end joining 
PARP 
poly(ADP-ribose) polymerase 
PFS 
progression-free survival 
P-gp 
P-glycoprotein  
PK 
Pharmacokinetics 
PRO 
patient reported outcomes 
PS 
performance status 
QD 
once a day 
QTc 
corrected QT interval  
SAE 
serious adverse event 
TEAES 
treatment-emergent adverse events 
ULN 
upper limit of normal 
 
 


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1 INTRODUCTION 
 Study Design 
 
This study will be conducted using a Bayesian Optimal Interval (BOIN) design with a 
target rate of dose limiting toxicities (DLT) set at 0.3.  The BOIN design chooses the 
dose of study drug utilized for new patients based on the already observed incidence 
of toxicities. If the toxicity rate at the current dose is low, dose will be increased, 
whereas, the dose will be de-escalated if the observed toxicity rate is high. 
Additional patients will be treated as long as the observed toxicity rate remains 
indeterminate. For the purposes of this study, two dose levels of niraparib (100mg 
and 200 mg) will be evaluated concomitant with the concurrent administration of 
pelvic radiotherapy. Enrollment continues until 17 patients are enrolled at a safe 
dose for efficacy evaluation. A treatment scheme that outlines use of both pelvic 
radiotherapy and niraparib is found in Fig. 1. Study drug will be initiated at a dose of 
100mg and escalate / de-escalate according to criteria specified in Table 2. This 
combination Phase I/II design ensures enrollment of the required number of patients 
for efficacy endpoint, while continuously monitoring safety, ensuring correct selection 
of the maximum tolerated dose (MTD) and allocation of maximum number of 
patients to the MTD group. 
 
Figure 1: 
 
 
 
 
 
 
 
 
 
 
 
 
Diagnosed with 
metastatic 
cervical cancer 
3 – 6 cycles any 
platinum-based 
chemotherapy 
Signed consent, CT & pelvic 
exam ECOG 0 or 1 and 
CR/PR 
ENROLL 
ON TRIAL 
External beam XRT + niraparib 
concurrently (5 weeks) 
Niraparib 
concurrently 
(hold on HDR 
Brachytherapy 
Week 1 
Week 2 
Week 3 
Week 4 
Week 5 
Week 6 
Week 7 
Niraparib alone x 1 
month 
Weekly PE, CBC, QOL and AE monitoring 
Pelvic exam, CBC, 
ECOG 0-2 and 
CR/PR, consider 
continuing niraparib 


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 Primary Objective 
A. To establish the maximum tolerated dose (MTD) of niraparib when 
administered concurrently with whole pelvic radiotherapy. 
 
B. Determine the local (pelvic) control for patients with metastatic cervical 
cancer treated with definitive pelvic radiotherapy. 
 Secondary Objectives 
A. Assess the acute toxicity profile of niraparib administered concurrently with 
whole pelvic radiotherapy. 
  
B. Assess quality of life for women receiving niraparib concurrently with whole 
pelvic radiotherapy.  
 
C. Assess tumor response outside the radiation field for women receiving 
niraparib concurrently with whole pelvic radiotherapy.  
 
 Correlative Objectives 
Pharmacodynamics (PARP Testing and percent inhibition by niraparib) 
 


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2 BACKGROUND AND SIGNIFICANCE  
 Background of PARP and Homologous Recombination Deficiency 
Poly(ADP-ribose) polymerase (PARP)1 and PARP2 are zinc-finger deoxyribonucleic 
acid (DNA)-binding enzymes that play a crucial role in DNA repair.1 Upon formation 
of DNA breaks, PARP binds at the end of broken DNA strands, a process that 
activates its enzymatic activity. 
Activated PARP catalyzes the addition of long polymers of adenosine diphosphate 
(ADP)-ribose onto PARP and several other proteins associated with chromatin, 
including histones and various DNA repair proteins.2,3 This results in chromatin 
relaxation, fast recruitment of DNA repair proteins, and efficient repair of DNA 
breaks. In this manner, PARP plays a key role in sensing DNA damage and 
converting it into intracellular signals that activate the base excision repair (BER) 
and single-strand break repair pathways. Normal cells repair up to 10,000 DNA 
defects daily, and single-strand breaks are the most common form of DNA damage. 
Cells that are unable to repair this burden of DNA damage, such as those with 
defects in the homologous recombination or BER pathways, are at risk for 
accumulating multiple lesions that will ultimately trigger apoptosis. They enter the S 
phase (DNA replication) of the cell cycle with unrepaired single- and double-strand 
breaks. Pre-existing single-strand breaks are converted to double-strand breaks as 
the replication machinery passes. Accumulated double-strand breaks present during 
S phase are repaired by homologous recombination. Homologous recombination is 
the preferred repair pathway because it is associated with a much lower error rate 
than other forms of repair. Cells that are unable to perform DNA repair via 
homologous recombination (e.g., due to inactivation of genes required for 
homologous recombination, such as breast cancer [BRCA1]- or breast cancer 2 
[BRCA2]-mutated cells) are at risk for accumulating multiple lesions that will 
ultimately trigger apoptosis. These cells accumulate stalled replication forks during S 
phase and are more likely to use the error-prone nonhomologous end joining (NHEJ) 
or alternative (alt)-NHEJ pathways to repair double-strand breaks in DNA. 
Accumulation of errors in DNA by NHEJ contributes to mutation burden that 
promotes the development of cancer. Over time, the buildup of excessive DNA 
errors in combination with the inability to complete S phase (because of stalled 
replication forks) contributes to cell death.2,3 
Treatment with PARP inhibitors could represent a novel opportunity to selectively kill 
a subset of cancer cells with deficiencies in DNA repair pathways. For example, a 
tumor arising in a patient with a germline BRCA mutation (gBRCAmut) has a 
defective homologous recombination DNA repair pathway and would be increasingly 
dependent on NHEJ, alt-NHEJ, and BER for maintenance of genomic integrity. 
PARP inhibitors block alt-NHEJ and BER, forcing tumors with BRCA deficiencies to 
use the error-prone NHEJ to fix double-strand breaks.1 Non-BRCA deficiencies in 
homologous recombination DNA repair genes could also enhance tumor cell 
sensitivity to PARP inhibitors.4 The rationale for anticancer activity in a subset of 


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non-gBRCAmut tumors is that they share distinctive DNA repair defects with 
gBRCAmut carriers, a phenomenon broadly described as “BRCAness.”5 DNA repair 
defects can be caused by germline or somatic alterations to the homologous 
recombination DNA repair pathway. In a recent analysis of approximately 500 high-
grade serous ovarian adenocarcinoma tumors, approximately 50% contained 
homologous recombination defects.6 A subset of these tumors had biologically 
plausible molecular alterations that may make them sensitive to PARP inhibition by 
niraparib. A similar analysis of triple-negative breast cancer indicates that 43% to 
44% of these patients have tumors with homologous recombination defects.7 
Homologous recombination is a complex pathway, and several genes other than 
BRCA1 and BRCA2 are required either to sense or repair DNA double-strand breaks 
via the homologous recombination pathway. Therefore, PARP inhibitors are also 
selectively cytotoxic for cancer cells with deficiencies in DNA repair proteins other 
than BRCA1 and BRCA2.1,5,8  
Recent clinical studies have shown PARP inhibitors to be active in breast and 
ovarian cancer. Clinical anticancer activity with PARP inhibitors has been seen in 
both patients with gBRCAmut and without gBRCAmut; however, activity is more 
robust in patients with the germline mutation.1,4,9-15 In summary, treatment with 
PARP1/2 inhibitors represents a novel opportunity to selectively kill a subset of 
cancer cell types by exploiting their deficiencies in DNA repair. Human cancers 
exhibit genomic instability and an increased mutation rate due to underlying defects 
in DNA repair. These deficiencies render cancer cells more dependent on the 
remaining DNA repair pathways, and targeting these pathways is expected to have a 
much greater impact on the survival of the tumor cells than that of normal cells. 
 Background of Niraparib 
Niraparib is a potent, orally active PARP1 and PARP2 inhibitor developed as a 
treatment for patients with tumors that harbor defects in the homologous 
recombination DNA repair pathway or that are driven by PARP-mediated 
transcription factors.  It was granted fast track designation by the FDA and approved 
on March 27, 2017 in the US for the maintenance treatment of adult patients with 
recurrent epithelial ovarian, fallopian tube, or primary peritoneal cancer who are in 
complete or partial response to platinum based chemotherapy. 
2.2.1 
Non-clinical Experience  
Nonclinical data on niraparib are discussed in detail in the niraparib Investigator’s 
Brochure (IB). Briefly, in nonclinical models, niraparib has been observed to inhibit 
normal DNA repair mechanisms and induce synthetic lethality when administered to 
cells with homologous recombination defects. In a BRCA1-mutant xenograft study, 
niraparib dosed orally caused tumor regression, which was mirrored by a >90% 
reduction in tumor weight compared with control. In a BRCA2-mutant xenograft 
study, niraparib-dosed mice showed 55% to 60% growth inhibition, both by tumor 
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Niraparib displayed strong antitumor activity in in vivo studies with BRCA1-mutant 
breast cancer (MDA-MB-436), BRCA2-mutant pancreatic cancer (CAPAN-1), and 
with patient-derived Ewing sarcoma mice models. Utilizing patient-derived ovarian 
and breast cancer xenograft models, niraparib demonstrated response in both 
BRCAmut and BRCA wild-type tumors. 
2.2.2 
Clinical Experience  
2.2.2.1 Phase 1 Study of Niraparib Monotherapy in Advanced Solid Tumors 
Niraparib clinical data are discussed in detail in the niraparib IB. In the Phase 1 
clinical program, niraparib, as a monotherapy or in combination with chemotherapy, 
has been administered to 144 patients. 
2.2.2.2 Phase 1 Study of Niraparib Monotherapy in Advanced Solid Tumors 
Clinical activity data for niraparib administered as monotherapy in patients with 
ovarian cancer are available from 1 early-phase clinical study. In Parts A and B of 
the Phase 1 study PN001 (ClinicalTrials.gov identifiers: MK-4827-001 and 
2008_501), 100 patients with advanced solid tumors who had received a median of 
3 prior therapies were enrolled; 49 patients had ovarian cancer (13 platinum-
sensitive, 35 platinum-resistant, and 1 platinum-refractory).11 An additional 4 patients 
were enrolled in Part D of the study, which assessed pharmacokinetics only.60  
The most common nonhematological TEAEs were nausea, fatigue, anorexia, 
constipation, vomiting, and insomnia. These TEAEs were mainly mild to moderate in 
severity, self-limiting, and manageable with standard treatments. Hematological 
toxicity appeared to be dose proportional and most frequently arose in the setting of 
cumulative doses. Anemia was reported in 48 (48%) of 100 patients and was Grade 
≥3 in 10 (10%) of 100 patients. Thrombocytopenia was less common (35 [35%] of 
100 patients) and was Grade ≥3 in 15 (15%) of 100 patients. Neutropenia was the 
least commonly reported (24 [24%] of 100 patients), and was Grade 3 in 4 (4%) of 
100 patients at niraparib doses of 300 and 400 mg. In all cases, hematological 
TEAEs were uncomplicated and reversible. Twenty patients required dose 
reductions (usually by 1 dose level) for recurrent anemia or thrombocytopenia. 
Treatment was discontinued due to AEs in 7 patients, including the 4 patients who 
had DLTs during the first cycle and 3 patients who had Grade 3 vomiting, Grade 2 
prolongation of QT interval, and Grade 3 prolongation of QT interval. No treatment-
related deaths occurred. 
Of the 49 patients, 22 had confirmed BRCA1 or BRCA2 mutation, of whom 20 were 
radiologically assessable. Eight (40%) of these 20 patients achieved a confirmed 
partial response (PR) by Response Evaluation Criteria in Solid Tumors (RECIST) 
and cancer antigen 125 (CA-125) Gynecologic Cancer Intergroup criteria at doses 
ranging from 80 to 400 mg per day. Median response duration was 387 days (range: 
159 to 518 days). Three (33%) of 9 patients with platinum-resistant BRCAmut 
ovarian cancer had PR by RECIST and CA-125 criteria. In patients with platinum-


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sensitive disease, 5 (50%) of 10 patients (95% CI: 19 to 81) with BRCA1 or BRCA2 
mutations had RECIST and CA-125 responses. 
2.2.2.3 Phase 3 Study of Niraparib Monotherapy in Platinum-sensitive, 
Recurrent Ovarian Cancer 
In the randomized, double-blind, Phase 3 NOVA trial (Niraparib Maintenance 
Therapy in Platinum-Sensitive, Recurrent Ovarian Cancer), a total of 553 patients 
were randomized at 107 centers worldwide. Patients were categorized according to 
the presence or absence of a gBRCAmut (gBRCA cohort and non-gBRCA cohort) 
within their tumors and the type of non-gBRCAmut and were randomly assigned in a 
2:1 ratio to receive niraparib (300 mg) or placebo once daily (QD). The primary end 
point was progression-free survival (PFS). A total of 203 patients were enrolled in 
the gBRCAmut cohort and 350 patients in the non-gBRCAmut cohort. Among the 
350 patients in the non-gBRCAmut cohort, 162 tumors were identified as 
homologous recombination deficiency positive (HRDpos), and 134 had tumors that 
were HRD negative (HRDneg). HRD status was assessed as indeterminate for 54 
patients. 
Demographic and baseline characteristics were well balanced.  Table 1 below 
shows the results for the PFS primary endpoint for each of the 3 primary efficacy 
populations (i.e., gBRCAmut cohort, HRDpos cohort, and overall non-gBRCAmut 
cohort). In addition, median PFS in patients with HRDneg tumors was 6.9 months 
(95% confidence interval [CI]: 5.6, 9.6) in the niraparib arm, versus 3.8 months (95% 
CI: 3.7, 5.6) in the placebo arm, with a HR of 0.58 (95% CI: 0.361, 0.922) (p = 
0.0226). 
 
Table 1: Progression-Free Survival in Ovarian Cancer Patients in NOVA 
 
gBRCAmut Cohort 
Non-gBRCAmut Cohort 
(Regardless of HRD 
Status) 
HRDpos (Within 
non-gBRCAmut 
Cohort) 
 
Niraparib 
(n = 138) 
Placebo 
(n = 65) 
Niraparib 
(n = 234) 
Placebo 
(n = 116) 
Niraparib 
(n = 106) 
Placebo 
(n = 56) 
Median PFS (95% CI)a 
21.0 
(12.9, 
NE) 
5.5 
(3.8, 7.2) 
9.3 
(7.2, 11.2) 
3.9 
(3.7, 5.5) 
12.9 
(8.1, 15.9) 
3.8 
(3.5, 5.7) 
p-valueb 
< 0.0001 
< 0.0001 
< 0.0001 
HR (niraparib: 
placebo) (95% CI)c 
0.27 
(0.173, 0.410) 
0.45 
(0.338, 0.607) 
0.38 
(0.243, 0.586) 
Source: PR-30-5011-C (NOVA main) CSR 
Abbreviation: CI = confidence interval; CSR = clinical study report; gBRCAmut = germline BRCA 
mutation; HR = hazard ratio; HRD = homologous recombination deficiency; HRDpos = homologous 
recombination deficiency positive; NE = not evaluated; PFS = progression-free survival. 
a PFS is defined as the time in months from the date of randomization to progression or death. 
b Based on stratified log-rank test using randomization stratification factors. 


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c Based on the stratified Cox proportional hazards model using randomization stratification factors. 
 
The primary data to support the safety of treatment with niraparib are derived from 
the NOVA main study in which a total of 546 patients received study treatment. 
All 367 patients who received niraparib and 171 (96%) of 179 patients who received 
placebo experienced at least 1 treatment-emergent adverse event (TEAE). The high 
rate of TEAEs in the placebo group indicates the burden of prior chemotherapy and 
the patient’s underlying ovarian cancer. Review of the data across study cohorts for 
TEAE incidence showed that, in general, the results were similar in the gBRCAmut 
and non-gBRCAmut cohorts. In the overall safety population, for the niraparib versus 
placebo treatment arms, the incidences of Grade 3 or 4 TEAEs (74% vs. 23%), 
serious adverse events (SAEs) (30% vs. 15%), TEAEs leading to treatment 
interruption (67% vs. 15%), TEAEs leading to dose reduction (69% vs. 5%), and 
TEAEs leading to treatment discontinuation (15% vs. 2%) were higher for niraparib 
than for placebo. There were no on-treatment deaths reported. 
The most commonly observed nonhematologic TEAEs (all grades) observed in 
niraparib-treated compared with placebo-treated patients were nausea (74% vs. 
35%), fatigue (46% vs. 32%), constipation (40% vs. 20%), and vomiting (34% vs. 
16%). The majority of the nonhematological TEAEs were mild to moderate in 
severity. The most commonly observed hematologic TEAEs (all grades) of niraparib 
were anemia (49%), thrombocytopenia (46%), decreased platelet count (20%), and 
neutropenia (18%). Although Grade 3 or 4 hematologic laboratory AEs were 
common at the initiation of study treatment, no severe clinical sequelae were 
observed, and relatively few patients discontinued study treatment due to these AEs. 
Dose adjustment based on individual tolerability during the first 3 cycles substantially 
reduced the incidence of these AEs beyond Cycle 3, indicating the overall 
effectiveness of the approach to dose modification. These TEAEs can be monitored 
routinely using standard assessments of hematological laboratory parameters, as is 
routine for patients with ovarian cancer receiving anticancer therapies. In the NOVA 
study, niraparib dose adjustment tended to occur early with most patients reaching 
their individual adjusted dose level at the end of Month 3 (i.e. Cycle 3) of treatment. 
Myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML) have been 
observed in patients receiving treatment with olaparib, a PARP inhibitor; given the 
common mechanism of action, MDS and AML therefore represent a potential risk to 
patients receiving niraparib. In the Phase 3 NOVA study, the incidence of MDS/AML 
in patients who received niraparib (5 of 367; 1.4%) was similar to its incidence in 
patients who received placebo (2 of 179; 1.1%). Guidance on monitoring patients for 
new AEs of MDS/AML and the follow-up of patients with suspected MDS/AML is 
provided. 
Study PR-30-5011-C1 (NOVA corrected QT interval [QTc] substudy; n = 26) is an 
open-label evaluation of the effects of niraparib on QTc measurements in patients 
with histologically diagnosed ovarian cancer, fallopian tube cancer, or primary 
peritoneal cancer. There were no reports of clinically significant abnormal 


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electrocardiogram (ECG) changes, including QTc interval prolongation, attributed to 
niraparib. Administration of niraparib at the therapeutic dose did not prolong the QT 
interval. There was no correlation between the exposure level (i.e. plasma 
concentration) of niraparib and QTc changes (i.e. change in corrected QT interval 
calculated using Fridericia’s formula [ΔQTcF]).    
 Rationale for Current Study 
Invasive carcinoma of the uterine cervix is the fourth most common cancer 
diagnosed in women worldwide. Each year, more than 528,000 women are newly 
diagnosed with an invasive cervical cancer. More than 266,000 deaths occur 
annually as a result of this disease1.  Regions with the highest incidence are located 
in parts of Africa, Latin America and the Caribbean that lack population-based 
screening programs. Collectively, nearly 84% of invasive carcinomas of the cervix 
are diagnosed in less developed parts of the world where screening is not readily 
available. In the United States, there are 13,000 new cases and 7,000 deaths due to 
an invasive carcinoma of the cervix annually. Unfortunately, the burden of cervical 
cancer disproportionately impacts disadvantaged communities where routine access 
to screening is often limited.2   
 
Patients with early-stage disease are curable with surgery and/or chemoradiation. 
About 50% of women in the United States presenting with cervical cancer will 
present with localized disease requiring chemoradiation3. Platinum-based 
chemotherapy is considered the gold standard for concurrent chemosensitization4-7. 
In a recent meta-analysis, the addition of sensitizing chemotherapy improved the 5 
year overall survival rate by 6% (HR 0.81: 60 vs 66%). Two year progression-free 
survival is approximately 80% for women who concurrently receive sensitizing doses 
of cisplatin, but only 70% for those who do not.8 However, the addition of cisplatin-
based chemotherapy increases the incidence of acute hematological and 
gastrointestinal toxicities that not infrequently preclude completion of standard of 
care chemoradiation. In the Rose, et al, study, for example, only 49% of women 
were able to complete all 6 intended cycles of cisplatin6. At present, the best 
strategy for managing distantly metastatic (e.g. disease occurring in the 
mediastinum or supraclavicular nodal basin) is unclear. Our institutional standard for 
women with disease outside standard pelvic and para-aortic radiation fields has 
been to administer 3-6 cycles of combination platinum-based chemotherapy. We 
then offer definitive radiotherapy to patients who experience a partial or complete 
response to chemotherapy treatment. Our initial analyses of the National Cancer 
Database (NCDB) indicate that this treatment plan significantly improves the survival 
of Stage IV cervical cancer patients. 
2.3.1 Rationale for Study Population 
The most effective strategy for managing distantly metastatic invasive carcinomas of 
the cervix (e.g. disease occurring in the mediastinum, bone, or supraclavicular nodal 
basin) is not defined. In the absence of nationally accepted guidelines, our 
institutional standard for women diagnosed with disease outside standard pelvic and 


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para-aortic radiation fields has been 3-6 cycles of induction-style carboplatin and 
paclitaxel.  Whole pelvic radiotherapy is then offered for patients with good 
performance status who experience a partial or complete disease response to 
chemotherapy. Based on the success of niraparib in breast and ovarian cancer trials 
and the concern for toxicities and comorbidities limiting the compliance of concurrent 
cisplatin for cervical cancer, we propose a phase I/II study of women diagnosed with 
metastatic (Stage IV) disease to evaluate the safety, tolerability and preliminary 
efficacy of Niraparib when administered concurrently with definitive regional 
radiotherapy for treatment of cervical cancer. 
2.3.2 Rationale for Objectives 
Niraparib, an orally available small molecule PARP inhibitor, has been well-tolerated 
in Phase I/II dose-escalation trials, and is currently being investigated in Phase III 
trials as monotherapy for advanced breast cancer patients. At present, there is no 
clinical trial data available to determine whether niraparib can be safely administered 
concurrently with radiation. The fundamental hypothesis of this proposal is that 
niraparib can be effectively used to sensitize invasive cervical cancers to 
radiotherapy. Here, we propose a prospective, hybrid Phase I/II dose study to 
evaluate the safety and efficacy of niraparib as a potential radio-sensitizer in 
platinum sensitive patients. The Phase I component of this study will be used to 
determine a safe and tolerable dose of niraparib that can be administered 
concurrently with definitive regional radiotherapy for treatment of metastatic cervical 
cancer. The subsequent Phase II component will then evaluate the efficacy of this 
combination regimen, as measured in time to local disease progression.   
 
The primary objective of the Phase I component is to determine the maximally 
tolerated dose (MTD) of niraparib when given concurrently with pelvic radiotherapy.  
The primary outcome of the Phase II component is defined as time to pelvic (local) 
control for patients who have received niraparib with pelvic radiation as part of their 
treatment for a metastatic cervical cancer. Progression will be clinically defined as 
local (pelvic) disease growth, as this is a standard measure of effect in cervical 
cancer. 
2.3.3 Rationale for Measures 
Maximum tolerated dose (MTD) is the highest dose of niraparib that does not cause 
unacceptable side effects as defined as Dose Limiting Toxicity (DLT) in more than 
30% of patients; see Section 4.8. Toxicity will be reported as the frequency and 
grade of each toxicity determined using CTCAE, Version 4. 
 
For the efficacy analysis, we evaluate the effectiveness of concurrent niraparib by 
measuring local progression free survival, which is the standard measure in cervical 
cancer.  Local (pelvic) control will allow for evaluation of Niraparib as a 
radiosensitizer as the radiation will be directed to the pelvic tumor. Recurrence will 
be determined as the time from baseline CT or PET-CT date to pathologic or 


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radiologic diagnosis of any local or distant disease, receipt of any additional anti-
cancer therapy, or death from any cause.  Response and progression will be 
evaluated in this study using the new international criteria proposed by the 
Response Evaluation Criteria in Solid Tumors (RECIST) Committee (Version 1.1).  
Changes in only the largest unidimensional measurement (diameter) of index tumor 
lesions are used to assess response by RECIST criteria.   
 
Quality of life will be used to determine the prevalence and duration of acute and 
long-term symptoms and symptom scores using FACT-Cx.  
 


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3 PARTICIPANT SELECTION 
3.1 Inclusion Criteria 
a. Participant must have histologically confirmed diagnosis of invasive 
squamous cell or adenocarcinoma of the cervix, FIGO Stage IIIC2 or IV (see 
Appendix 5) 
b. Participant must have an Eastern Cooperative Oncology Group (ECOG) 
performance status of ≤ 1 
c. Participant must be ≥ 18 years of age 
d. Participant must have adequate organ function within 28 days of registration, 
defined as follows: 
 Absolute neutrophil count ≥ 1,500/µL 
 Platelets ≥ 100,000/µL 
 Hemoglobin ≥ 9 g/dL 
 Serum creatinine ≤ 1.5 x upper limit of normal (ULN) or calculated 
creatinine clearance ≥ 30 mL/min using the Cockcroft-Gault equation 
 Total bilirubin ≤ 1.5 x ULN (≤2.0 in patients with known Gilberts syndrome) 
OR direct bilirubin ≤ 1 x ULN 
 Aspartate aminotransferase and alanine aminotransferase ≤ 2.5 x ULN 
unless liver metastases are present, in which case they must be ≤ 5 x 
ULN  
e. Participant receiving corticosteroids may continue as long as their dose is 
stable for least 4 weeks prior to initiating protocol therapy 
f. Participant must agree to not donate blood during the study or for 90 days 
after the last dose of study treatment 
g. Female participant of childbearing potential must have a negative serum 
pregnancy test within14 days prior to registration. Pregnancy test should be 
repeated within 7 days before CT simulation if more than 14 days has 
passed since the previous pregnancy test. (If serum test is falsely positive, 
pregnancy can be excluded by appropriate pelvic imaging.) Patient must 
agree to abstain from activities that could result in pregnancy from screening 
through completion of 7 days of pelvic radiotherapy. Females of non-
childbearing potential is defined as follows (by other than medical reasons): 
 ≥45 years of age and has not had menses for >1 year 
 Post-hysterectomy, post-bilateral oophorectomy, post external beam 
radiation of 6 Gy to the pelvis, or post-tubal ligation. Documented 
hysterectomy or oophorectomy must be confirmed with medical records 
of the actual procedure or confirmed by a physical exam or imaging. 
h. Participant must agree to not breastfeed during the study and for 180 days 
after the last dose of study treatment 


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i. Participant must be able to understand the study procedures and agree to 
participate in the study by providing written informed consent 
j. Participant must have completed 3-6 cycles of platinum based chemotherapy 
(acceptable regimens in Appendix 7) with clinical evidence of CR (complete 
response) or PR (partial response) by RECIST criteria no less than 4 weeks 
and no greater than 12 weeks prior to initiation of protocol therapy.  If 
bevacizumab used, 6 weeks must elapse between administration of 
bevacizumab and start of radiation therapy. 
k. Participant must be eligible for chemoradiation treatment in the opinion of the 
treating investigator  
l. Participants who are HIV+ must have CD4 counts >200/dL and demonstrate 
documented HAART compliance 
m. Chemotherapy-related hematological toxicities must have resolved to Grade 
1 or less  
n. Participant must have had a CT (chest/abdomen/pelvis) or PET-CT, within 
56 days of registration 
 Exclusion Criteria 
a. Participant must not be simultaneously enrolled in any interventional clinical 
trial 
b. Participant must not have known documented intra-uterine pregnancy 
c. Participant must not have had major surgery ≤ 3 weeks prior to initiating 
protocol therapy and participant must have recovered from any surgical 
effects 
d. Participant must not have received an investigational therapy ≤ 4 weeks, or 
within a time interval less than at least 5 half-lives of the investigational agent, 
whichever is shorter, prior to initiating protocol therapy.  Participant that has 
received prior treatment with a PARP inhibitor is excluded from this study 
e. Participant last treatment with platinum based chemotherapy was ≥12 weeks 
from initiation of protocol therapy 
f. Participant must not receive any additional chemotherapy while on study 
g. Participant has had radiation therapy encompassing >20% of the bone 
marrow within 2 weeks; or any radiation therapy within 1 week prior to Day 1 
of protocol therapy 
h. Participant must not have a known hypersensitivity to niraparib components 
or excipients 
i. Participant must not have received colony-stimulating factors (e.g. 
granulocyte colony-stimulating factor, granulocyte macrophage 


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colony-stimulating factor, or recombinant erythropoietin) within 4 weeks prior 
initiating protocol therapy 
j. Participant must not have any known history of myelodysplastic syndrome 
(MDS) or acute myeloid leukemia (AML)  
k. Participant must not have a serious, uncontrolled medical disorder, 
nonmalignant systemic disease, or active, uncontrolled infection. Examples 
include, but are not limited to, uncontrolled ventricular arrhythmia, NYHA 
Class III/IV heart failure, recent (within 90 days) myocardial infarction, 
uncontrolled major seizure disorder, or any psychiatric disorder that prohibits 
obtaining informed consent. Participant must not have had a CVA within 6 
months of registration 
l. Participant must not have had diagnosis, detection, or treatment of another 
type of cancer ≤ 2 years prior to initiating protocol therapy (except basal or 
squamous cell carcinoma of the skin that has been definitively treated) 


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4 TREATMENT PLAN 
 Method of Treatment Assignment 
Phase I component will evaluate safety for two dose levels of niraparib (100 mg and 
200 mg) for use with concurrent pelvic radiotherapy. The dose assignments are 
shown in Table 2, based on DLT events. 
 
Initial treatment dose is 100 mg, and then every 3 patients the dose is escalated if 
the observed toxicity rate at the current dose is low, de-escalated if the observed 
toxicity rate is high, and additional patients are treated if the observed toxicity rate is 
between indeterminate. Participants will continue to be enrolled and assigned to 
treatment dose according to these rules until 17 efficacy evaluable participants are 
enrolled to any single dose level. 
 
 
Table 2: DLT Regulation of Dose Escalation and De-Escalation 
Number of patients treated 
3 
6 
9 
12 
15 
18 
Escalate if number of DLT <= 
0 
1 
2 
2 
3 
4 
Treat additional 3 pts on current dose if number of DLT= 
1 
2 
3 
3, 4 
4, 5 
5, 6 
Deescalate* if number of DLT >= 
2 
3 
4 
5 
6 
7 
Eliminate** if number of DLT >= 
3 
4 
5 
7 
8 
9 
* At the lowest dose level, if the recommendation is to de-escalate AND the dose level has not been eliminated 
from consideration, 3 additional pts will be accrued at the same dose level; otherwise the trial will stop. 
** Eliminate dose level and all higher doses from further use.  
 
Initial treatment dose is 100 mg, and will be escalated to 200 mg per Table 2 
 
Radiation with niraparib must start within 12 weeks of finishing platinum based 
chemotherapy.  If bevacizumab is used, a minimum of 6 weeks of time must have 
elapsed between the last cycle of bevacizumab and the start of radiation. 
 
Niraparib will be administered continuously on a daily basis starting the same day as 
the start of radiation and continued through 28 days after completion of radiation.  
Niraparib dosing will be held on days of brachytherapy administration and resume 
the following day.    
 
At that time, participant may continue on maintenance niraparib (28-day cycles) if 
the following criteria are met:  
 No evidence of progressive disease (clinical disease assessment) 
 Adequate performance status (0-2) 


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 If, in the opinion of treating investigator, participant has tolerated niraparib 
treatment adequately. 
 
Maintenance niraparib may be continued until evidence of disease progression or 
unacceptable toxicities, based on assessments every 28 day cycle.  
 Treatment Regimen 
Niraparib will be administered as a flat-fixed (100 mg or 200 mg), continuous daily 
dose.  The only exception is during brachytherapy administration occurring during 
radiation therapy.  Niraparib dosing will be interrupted on these days and resume the 
following day. Niraparib should be swallowed whole and not opened, crushed or 
chewed. Food does not significantly affect the absorption of niraparib; therefore, 
niraparib may be taken without regard to meals. Participants should take doses at 
approximately the same times each day.  Bedtime administration may be a potential 
method for managing nausea. Vomited doses should not be replaced or made up by 
altering the subsequent dose of medication taken or shortening the intervals 
between future doses. 
If a participant misses a dose (greater than 12 hours from normal dosing time) of 
niraparib, they should skip that dose and take their next dose at its regularly 
scheduled time.   
If niraparib is dose reduced, participants should be instructed to continue using their 
current supply at their new dose until their supply has been exhausted.  
Participants must be instructed to return unused study drugs to the site at 
discontinuation or completion of treatment. The site personnel must ensure that the 
appropriate dose of study drug is dispensed. 
4.2.1 
Other Agent Administration 
Radiotherapy consisting of whole pelvic radiotherapy with extended field 
radiotherapy will be administered to all patients as per institutional standard care. 
Radiotherapy to disease outside the pelvic or para-aortic field will be at the 
discretion of the treating physician.  Extended field radiotherapy will also be 
administered to those subjects with documented radiologic evidence of common iliac 
or para-aortic lymphadenopathy. Intensity modulated radiotherapy (IMRT) will be 
used for all subjects, allowing definitive target coverage to be optimized while 
minimizing the radiation delivered to adjacent normal tissues, such as bone marrow. 
Here, use of IMRT should decrease both acute and chronic toxicity, as the use of 
IMRT has been previously shown to reduce the incidence of Grade 2 GI toxicities as 
well as the radiation dose delivered to active bone marrow in the pelvis. Treatment 
fields will be extended to the level of the renal vessels in cases where enlarged 
common iliac nodes have been identified, and to the diaphragmatic crura in cases of 
enlarged para-aortic nodes. This will consist of 45-50 Gy delivered in 1.8-2 Gy 
fractions, delivered with IMRT technique. Specific dose fractions used will be left to 
the discretion of the treating physician as long as mean bone marrow dose remains 


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under 36 Gy, concomitant as well as sequential nodal boost is permitted for node-
positive patients. Treatments will be given on a daily basis, for 5 days a week. 
Brachytherapy will be delivered via either intracavitary or interstitial techniques such 
that the total dose to the cervical disease is 80-90 Gy from a combination of external 
beam and brachytherapy. Use of standard intracavitary applicators: tandem and 
ovoids or tandem and rings as well as interstitial brachytherapy (as needed) will be 
acceptable.  The decision to use intercavitary radiation will be made at the time of 
initial imaging; i.e. if the disease would not be well covered by a standard tandem 
and ovoid implant, then interstitial needles will be considered.  HDR brachytherapy 
will be used for the majority of cases, however in the case of patient preference, 
LDR may be considered.  Computed tomography (CT) will be used to calculate 
dosimetry for the brachytherapy applications. All brachytherapy reporting will be 
performed as per ICRU guidelines, with the cumulative dose (external beam + 
brachytherapy) prescribed calculated in EQD2 to the high-risk clinical target volume 
(HR-CTV), bladder D2cc ≤90 Gy, rectal D2cc ≤ 75 Gy, bowel D2cc < 60 Gy, sigmoid 
D2cc<75 Gy.  Doses will be converted to EQD2 doses by the formula EQD2 = D x 
[(d + α/β)/(2 +  α/β)].  The following parameters will be recorded: D100 for HR-CTV, 
D90 for HR-CTV, V100 for HR-CTV. 
  
 Prohibited Therapies 
The following medications are prohibited while receiving protocol therapy: 
 Systemic anticancer or biological therapy. 
 Immunotherapy not specified in this protocol. 
 Chemotherapy not specified in this protocol. 
 Investigational agents other than niraparib 
 Any surgery that involves tumor lesions. Note: surgery done that involves 
tumor lesions will be considered as disease progression at the time the 
procedure is performed. 
 Niraparib weakly induces Cytochrome P450 (CYP)1A2 in vitro and is a 
relatively poor substrate for P-glycoprotein (P-gp); therefore, investigators 
are advised to use caution with the substrates for CYP1A2 with a narrow 
therapeutic range, i.e. theophylline and tizanidine.  
 Prophylactic cytokines (i.e. granulocyte colony-stimulating factor [GCSF]) 
should not be administered in the first cycle of the study but may be 
administered in subsequent cycles according to current American Society 
of Clinical Oncology (ASCO) guidelines.76  
 Birth Control 
Female participant of childbearing potential must have a negative serum pregnancy 
test within 14 days prior to registration. Pregnancy test should be repeated within 7 
days before CT simulation if more than 14 days has passed since the previous 


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pregnancy test. (If serum test is falsely positive, pregnancy can be excluded by 
appropriate pelvic imaging.) Patient must agree to abstain from activities that could 
result in pregnancy from screening through completion of 7 days of pelvic 
radiotherapy. Females of non-childbearing potential is defined as follows (by other 
than medical reasons): 
 ≥45 years of age and has not had menses for >1 year 
 Post-hysterectomy, post-bilateral oophorectomy, post external beam 
radiation of 6 Gy to the pelvis, or post-tubal ligation. Documented 
hysterectomy or oophorectomy must be confirmed with medical records 
of the actual procedure or confirmed by a physical exam or imaging. 
 Breast Feeding 
Participants must not breast-feed while receiving protocol therapy and for 180 days 
following the last dose of protocol therapy 
 Blood Donation 
Participants must not donate blood during the study or for 90 days after the last dose 
of protocol therapy. 
 Dose Escalation  
This study will be conducted using a Bayesian Optimal Interval (BOIN) design with a 
target DLT rate of 0.3 (Table 2). Two dose levels of niraparib (100mg, and 200 mg,) 
will be evaluated for use with concurrent pelvic radiotherapy. Study will begin at 
dose 100mg and escalate / de-escalate according to study design rules as per 
Section .1.and per Table 2. 
 Dose-Limiting Toxicity (DLT) 
4.8.1. DLT Definitions.  
The following adverse events occurring during concurrent radiation therapy 
and niraparib administration will be considered DLTs:  
 Any treatment-related Grade 4 non-hematologic clinical (non-laboratory) 
AE 
 Any treatment-related Grade 3 non-hematologic clinical (non-laboratory) 
AE (except fatigue) lasting >3 days despite optimal medical intervention 
 Any treatment-related Grade 3 or 4 non-hematologic laboratory 
abnormality if any of the following also occur: 
 The abnormality leads to hospitalization. 
 The abnormality persists for ≥7 days from the time of AE onset. 
 Any treatment-related hematologic toxicity defined as any of the following: 


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 Grade 4 thrombocytopenia for ≥14 days from the time of AE onset  
 Grade 3 or 4 thrombocytopenia associated with clinically significant 
bleeding 
 Grade 4 neutropenia for ≥7 days, Grade 3 or 4 neutropenia associated 
with infection, or Grade 3 or 4 febrile neutropenia 
 Any treatment-related toxicity leading to prolonged delay (>28 days) in 
initiating Cycle 3 of Niraparib 
 Any treatment-related toxicity leading to prolonged delay or withholding of 
radiation therapy (>2 days) 
 Any treatment-related Grade 5 AE 
 Any treatment related Grade 2 AE which is severely impacting the 
patient’s quality of life and the treating physician believes to be directly 
related to administration of niraparib, will be considered for dose reduction 
at the discretion of the treating physician and the patient. 
4.8.2. DLT Rules 
 
Niraparib dosing levels will be modified or halted as per study rules specified 
in Table 2.  
 
Dose modifications for participants are in Section 5 below.  
 Treatment Discontinuation  
Participants may continue protocol therapy until one of the following criteria applies: 
 Disease progression 
 Change in medical condition that deems the subject inappropriate for continued 
investigational therapy in the opinion of the treating investigator  
 Severe noncompliance with protocol as judged by the Investigator and/or Sponsor 
 Participant decision to withdraw 
 Participant becomes pregnant 
 Participant is diagnosed with MDS or AML (as confirmed by a hematologist) 
 Investigator, Sponsor, and/or TESARO becomes aware of conditions or events 
that suggest a possible risk or hazard to participants if the clinical study continues 
 Duration of Follow Up 
Participants will be followed for 12 months after removal from protocol therapy or until 
death, whichever occurs first.  Chart review will continue for 5 years from registration 
or until death, to evaluate for MDS/AML.  
 Discontinuation from Study 
Participants who discontinue from treatment will continue to be followed for overall 
survival until one of the following criteria apply: 


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 Withdrawal of consent 
 Lost to follow-up 
 Death from any cause 
 Termination of the study 
For participants who are thought to be lost to follow-up, at least 3 documented 
attempts will be made to contact the participant before she is deemed lost to follow-
up. These attempts will include at least 1 attempt via certified mail. 
 Participant Replacement Criteria 
Not applicable. 


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5 DOSE MODIFICATIONS 
 Niraparib 
 Treatment may be modified for any Common Terminology Criteria for Adverse 
Events (CTCAE) Grade 2 that the patient and treating physician believe to be 
severely impacting the patient’s QOL and the treating physician believes to be 
directly related to administration of niraparib. 
Treatment must be interrupted for any non-hematologic Common Terminology 
Criteria for Adverse Events (CTCAE) Grade 3 or 4 AE that the Investigator considers 
to be related to administration of niraparib (Table 4). If the nonhematologic toxicity is 
appropriately resolved to baseline or Grade ≤1 within 4 weeks (28 days) of the dose 
interruption period, the patient may restart treatment with niraparib but with a dose 
level reduction if prophylaxis is not considered feasible (see Table 4). If the event 
recurs at similar or worse grade, treatment should be interrupted again and, upon 
resolution, a further dose reduction must be made. No more than 1 dose reductions 
will be permitted (i.e. to a minimum dose of 100 mg QD – see Table 3).  
If the toxicity requiring dose interruption has not resolved completely or to CTCAE 
Grade 1 during the maximum 4-week (28-day) dose interruption period, and/or the 
patient has already undergone a dose reduction (to a minimum dose of 100 mg QD), 
the patient must permanently discontinue treatment with niraparib. 
The dose interruption and modification criteria for niraparib for hematologic 
parameters will be based on blood counts and are outlined in Table 5. If the 
hematologic toxicity has not recovered to the specified levels within 4 weeks (28 
days) of the dose interruption period, and/or the patient has already undergone a 
dose reduction (to a minimum dose of 100 mg QD), the patient must permanently 
discontinue treatment with niraparib. 
 
Table 3: Definition of Niraparib Dose Levels 
 
Event 
Dosea 
If Initial dose is at highest level 
200b mg QD 
DL-1: First dose reduction for treatment-related CTCAE Grade 3 or 4 AE or 
SAE where prophylaxis is not considered feasible (or Grade 2 at the 
discretion of the treating physician) 
100 mg QD 
Continued treatment-related CTCAE Grade 3 or 4 AE or SAE lasting >28 
days (or Grade 2 at the discretion of the treating physician) 
Discontinue 
niraparib. 
a Dose not to be decreased below 100 mg daily. 
b If the initial dose is below 200 mg, the same dose reduction principles will apply with fewer dose 
modification steps available. 
 


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Table 4: Niraparib Dose Modifications for Non-hematologic Adverse Reactions 
Abnormality 
Intervention 
Non-hematologic CTCAE ≥ Grade 3 adverse 
reaction where prophylaxis is not considered 
feasible or adverse reaction persists despite 
treatment 
Withhold niraparib for a maximum of 28 days or 
until resolution of adverse reaction. 
Resume niraparib at a reduced dose. Up to 1 dose 
reductions are permitted. 
CTCAE ≥ Grade 3 treatment-related adverse 
reaction lasting more than 28 days while patient is 
administered niraparib 100 mg/day 
Discontinue niraparib. 
 
Table 5: Niraparib Dose Modifications for Hematologic Toxicity 
Laboratory Abnormality 
Intervention 
Monitor complete blood counts weekly for the first month, monthly for the next 11 months of 
treatment, and periodically after this time. 
Platelet count < 75,000/μL 
First occurrence: 
Withhold niraparib for a maximum of 28 days and monitor blood 
counts weekly until platelet counts return to ≥75,000/μL. 
Resume niraparib at reduced dose.a 
 
Discontinue niraparib if the platelet count has not returned to 
acceptable levels within 28 days of the dose interruption period, 
or if the patient has already undergone dose reduction to 
100 mg QD. 
 
Neutrophil count < 1,000/μL 
Withhold niraparib for a maximum of 28 days and monitor blood 
counts until neutrophil counts return to >1,000/μL.  
Resume niraparib at a reduced dose.a 
Discontinue niraparib if neutrophil level has not returned to 
acceptable levels within 28 days of the dose interruption period, 
or if the patient has already undergone dose reduction to 100 
mg QD. 
Hemoglobin < 8 g/dL 
Withhold niraparib for a maximum of 28 days and monitor blood 
counts until hemoglobin returns to >8 g/dL.  
Resume niraparib at a reduced dose.a 
Discontinue niraparib if hemoglobin has not returned to 
acceptable levels within 28 days of the dose interruption period, 
or if the patient has already undergone dose reduction to 100 
mg QD. 
Any patient requiring transfusion of platelets or red blood cells 
(1 or more units) or hematopoietic growth factor support must 
undergo a dose reduction upon recovery if study treatment is 
resumed 


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Hematologic adverse reaction 
requiring transfusion 
For patients with platelet count ≤10,000/μL, platelet transfusion 
should be considered. If there are other risk factors such as 
co-administration of anticoagulation or antiplatelet drugs, 
consider interrupting these drugs and/or transfusion at a higher 
platelet count. 
Resume niraparib at a reduced dose once platelet count 
≥75,000.a 
Confirmed diagnosis of MDS or 
AML 
Permanently discontinue niraparib. 
a Niraparib dose must not be decreased below 100 mg daily. Additional details on dose reduction are 
described in Table 3 
In the case of thrombocytopenia, following the first occurrence, resumption of 
therapy may occur at the same dose or 1 dose level lower when the hematologic 
toxicity has resolved. Subsequent occurrences should trigger dose reduction upon 
resumption of therapy. If the platelet count has not reverted within 28 days of 
interruption to ≥75,000/μL, then study treatment should be discontinued. 
If dose interruption and/or modification is required at any point during study 
treatment because of hematologic toxicity, weekly blood draws for complete blood 
count (CBC) will be monitored until the AE resolves to the specified blood count 
levels as described in Table 5 above. To ensure the safety of the new dose, blood 
draws for CBC will be done as per study protocol. 
Any patient requiring transfusion of platelets or red blood cells (≥1 unit) must 
undergo a dose reduction upon recovery if study treatment is resumed. 
If a diagnosis of MDS/AML is confirmed by a hematologist, the patient must 
permanently discontinue study treatment. 
For major surgery while on study treatment, up to 4 weeks (28 days) of study 
treatment interruption is allowed.  
 


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6 PHARMACEUTICAL INFORMATION 
The investigator shall take responsibility for and shall take all steps to maintain 
appropriate records and ensure appropriate supply, handling, storage, distribution, 
and usage of these materials in accordance with the protocol and any applicable 
laws and regulations. 
 Niraparib 
6.1.1 Identity 
Niraparib ([3S]-3-[4-{7-(aminocarbonyl)-2H-indazol-2-yl} phenyl] piperidine [tosylate 
monohydrate salt]) is an orally available, potent, highly selective poly (adenosine 
diphosphate [ADP]-ribose) polymerase (PARP) -1 and -2 inhibitor. Niraparib is also 
known as ZEJULA. 
6.1.2 Potential Risks of Niraparib  
Reference the currently approved Investigational Brochure for niraparib to obtain 
safety, efficacy and potential risk information for the drug. 
6.1.3 Packaging, Labeling and Storage 
Niraparib is supplied by TESARO in high-density polyethylene (HDPE) bottles with 
child-resistant plastic closures. The study treatment will be open-label and will not be 
participant-specific. Detailed information on the product can be found in the 
Niraparib Storage and Handling Guidelines.  
 
All study treatment supplies must be stored in accordance with the manufacturer’s 
instructions and package labeling. Until dispensed to the participants, the study 
treatment will be stored and managed in an Investigational Pharmacy in compliance 
with GCP.   
6.1.4 Drug Accountability 
The Investigator or designee is responsible for maintaining accurate dispensing 
records of the study treatment throughout the clinical study. The study treatment 
accountability log includes information including a patient identifier, amount and date 
dispensed, and amount and date returned to the pharmacy, if applicable. Product 
returned to the pharmacy will be stored under the same conditions as products not 
yet dispensed but will be marked as 'returned' and kept separate from the products 
not yet dispensed. 
All dispensing and accountability records should be stored in accordance to the 
Sponsor-Investigator regulations. The pharmacist will dispense study treatment for 


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each participant according to the protocol and storage and handling manual, if 
applicable. 
6.1.5 Disposal and Destruction 
Niraparib will be destroyed at the investigational site at study conclusion and after all 
final drug accountability activities have been completed. 
 Other Agent 
Not applicable 


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7 CORRELATIVE STUDIES 
Table 6: Summary of Research Tissue and Blood Specimen Collection 
Research 
Sample 
Time point 
Contents 
Blood 
Cycle 1 Day 1 
 
Pre-Dose 
2 hours (+/- 15 min) post-dose 
  
 
 
2- 5mL EDTA Purple Top 
2- 5mL EDTA Purple Top  
Cycle 1  Day 8  
 
Pre-Dose (within 30 min of dose) 
2 hours (+/- 15 min) post-dose 
 
 
 
2- 5mL EDTA Purple Top  
2- 5mL EDTA Purple Top 
Cycle 1  Day 22  
 
Pre-Dose (within 30 min of dose) 
2 hours (+/- 15 min) post-dose 
 
 
 
2- 5mL EDTA Purple Top  
2- 5mL EDTA Purple Top 
 
 Pharmacodynamics (PARP Testing) 
Blood samples (10 cc total whole blood) will be collected in 2 (two) lavender top 
tubes on Days 1, 8, and 22 of niraparib treatment. For Cycle 1 Day 8 and Cycle 1 
Day 22, specimens will be collected both pre-dose (within 30 minutes of dose) as 
well as 120 + 15 minutes post-dose of niraparib. All specimens will be collected in 
EDTA lavender top tubes. Once collected, specimens will be placed on ice and 
transported to designated laboratories. After isolating peripheral blood mononuclear 
cells using standard clinical protocol, specimens will be flash frozen and stored at -
80̊ C until biochemical analysis of PARP activity is performed. At the time of 
batched analyses, specimens will be thawed and lysed, after which enzymatic 
PARP activity will be measured using a commercially available assay previously 
validated for this purpose (PARP In Vivo Pharmacodynamic Assay, Trevigen, Inc., 
Catalog #4520-096-K). All testing will be performed as in triplicate with results 
reported as mean percent inhibition of PARP1/2 activity at experimental time points 
(Day 1 post-dose and Days 8 and 22) compared to baseline (Day 1 pre-dose). 
Mean values with standard deviation will be calculated and reported for each time 
point. Two-tailed Student’s T-tests will be used to assess the statistical significance 
of observed differences. Associations between PARP inhibition and 12-month 
progression free survival will be evaluated using Kaplan Meier analysis where 
statistically feasible. Any specimens remaining after the conclusion of these 


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analyses will be preserved until study closure, after which they will be destroyed as 
per relevant institutional protocols. Bioanalytes prepared from these specimens will 
also be destroyed. 
 


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8 SCHEDULE OF ASSESSMENTS  
 Screening  
At Screening, the following procedures/tests will be performed: 
 Informed Consent 
 Review of Inclusion/Exclusion Criteria 
 ECOG Performance Status 
 Physical Exam 
 Pelvic Exam 
 HBV/HCV test 
 Medical History and concomitant medications 
 Vital Signs: systolic and diastolic blood pressures, weight and temperature 
 Height  
 Pregnancy testing within 14 days prior to registration; repeated as needed 
to comply with Inclusion/Exclusion Criteria 
 CBC with plat/diff 
 Comprehensive metabolic panel 
 CT (chest/abdomen/pelvis) or PET-CT, within 56 days of registration. 
 Baseline QOL assessment 
Please note that treatment with niraparib would not be scheduled to begin <4 weeks 
from most recent dose of cytotoxic chemotherapy (e.g. carboplatin and paclitaxel).  
 
 During Radiation (Niraparib given continuously) 
Radiation is given via external beam daily 5 days/week for 5 weeks and then 
brachytherapy for 2 weeks. Niraparib is given continuously on a 28 day cycle.  
Niraparib dosing will be held on days when brachytherapy is administered and dosing 
will resume the following day. 
 
The following procedures/tests will be performed on Day 1 (+/- 3 days) of each cycle:  
 
 Vital signs: systolic and diastolic blood pressures, weight, and temperature 
 Comprehensive metabolic panel 
 PARP testing: Days 1, 8, and 22. 


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 Assess for MDS/AML (assessed by chart review): Week 1 only 
The following procedures/tests will be performed weekly during concurrent radiation 
therapy and niraparib administration: 
 Physical Exam 
 CBC with plat/diff 
 Adverse event monitoring 
 QOL Assessment 
 Maintenance Therapy (after completion of radiation) 
The following procedures/tests will be performed at a study visit 28 days (+/- 7 days) 
after completing radiation therapy (XRT completion) and at each Maintenance visit 
(every 28-days):  
 
 Physical Exam 
 Pelvic Exam (only performed every 3 months) 
 Vital signs: systolic and diastolic blood pressures, weight, and temperature 
 CBC with plat/diff 
 Comprehensive metabolic panel 
 Adverse event monitoring 
 Review of concomitant medications (only at the completion of radiation 
therapy and XRT completion visit)  
 ECOG Performance Status (at XRT completion visit, and at least every 3 
months during maintenance) 
 QOL Assessment 
 Assess for MDS/AML (assessed by chart review) 
 End of Treatment 
The following procedures/tests will be performed at the End of Treatment visit, which 
must occur within 28 days (+/- 7 days) from the last administered dose of niraparib: 
 Adverse event monitoring 
 CBC with plat/diff 
 Comprehensive metabolic panel 


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 QOL Assessment (if the End of Treatment visit occurs during the 
maintenance phase) 
 Assess for MDS/AML (assessed by chart review) 
 Follow-up 
The following procedures/tests will be performed every 3 months (+/- 14 days) for one 
year from the end of treatment: 
 Physical Exam 
 Pelvic Exam 
 CBC with plat/diff 
 Comprehensive metabolic panel 
 Adverse event monitoring 
 CT (chest/abdomen/pelvis) or PET-CT 
 QOL Assessment 
 Assess for MDS/AML (assessed by chart review) 
 Long Term Follow-up  
The following procedures/tests will be performed every 12 months (+/- 2 months) for 
five years or until death, whichever occurs first: 
 Survival assessment  
 Assess for MDS/AML (assessed by chart review) 
 Unscheduled Assessments 
 SAE monitoring 
 If at any time after the study is completed, an Investigator becomes 
aware of an SAE that is considered related to the investigational 
product, the Investigator should report the SAE to the Sponsor-
Investigator and TESARO within 24 hours of becoming aware of the 
SAE 
 Clinical Laboratory Assessments 
 If dose interruption or modification is required at any point on study 
because of hematologic toxicity, weekly blood draws for CBC will be 
monitored until the AE resolves, and to ensure safety of the new dose, 
weekly blood draws for CBC also will be required for an additional 4 


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weeks after the AE has been resolved to the specified levels, after 
which monitoring every 4 weeks may resume 
 For any suspected MDS/AML case reported while a participant is 
receiving treatment or being followed for post-treatment assessments, 
bone marrow aspirate and biopsy testing must be completed by a local 
hematologist.  Testing completed as part of standard of care is 
sufficient. The study site must receive a copy of the hematologist’s 
report of aspirate/biopsy findings (which must include a classification 
according to World Health Organization criteria) and other sample 
testing reports related to MDS/AML. The site must keep a copy of the 
report with the participant’s study file. 


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9 STUDY CALENDAR 
Screening assessments are to be conducted within 28 days prior to registration unless 
otherwise specified in Inclusion/Exclusion Criteria.  Screening assessments occurring 
within 1 week prior to initiating study treatment do not need to be repeated on Cycle 
1 Day 1 unless otherwise specified.   
 
For women of childbearing potential, as defined in the eligibility criteria, a pregnancy 
test must be completed within 14 days of registration.  Pregnancy testing will be 
repeated within 7 days prior to CT simulation if it has been more than 14 days has 
elapsed since the last pregnancy test.     
 
Baseline assessments must be performed prior to administration of any study agent. 
See Study Calendar footnote A for relevant windows within which to perform all other 
protocol-dictated assessments.  


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Niraparib + Radiotherapy 
(Weekly)A  
Maintenance (after XRT)  
(28 Day Cycles) 
Follow-Up (after study 
drug) 
Long Term 
Follow up 
 
Base-
line 
W
k 
1 
W
k 
 2 
W
k 
3 
W
k 
4 
W
k 
5 
W
k 
6 
W
k 
7 
W
k 
8 
  
Post 
XRT (28 
days after 
treatment) 
Maintenance 
every 28-
daysC  
EOT VisitD   
Follow-Up, 
every 3 
months for 
1 yearE 
(Chart Review 
Only) 
Until 5 years 
after 
radiotherapy 
completion 
SCREENING 
Written Informed 
Consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/Exclusion 
Criteria 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
PHYSICAL 
Medical History,  
Previous 
MedicationsB 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Physical Exam 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
 
Vital Signs and 
Weight 
X 
X 
 
 
 
X 
 
 
 
X 
X 
 
 
 
Height  
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
ECOG 
Performance 
Status 
X 
 
 
 
 
 
 
 
 
X 
XM 
 
 
 
Pelvic Exam  
X 
 
 
 
 
 
 
 
 
X 
XQ 
 
X 
 
HBV/HCV test 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
LABORATORY 
CBC with plat/diff 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Comprehensive 
Metabolic PanelF 
X 
X 
 
 
 
X 
 
 
 
X 
X 
X 
X 
 
Pregnancy testG 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
ASSESSMENTS 
Adverse 
Events/ToxicityH 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Concomitant 
Medications 
X 
 
 
 
 
 
 
 
 
X 
 
 
 
 


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CT 
(chest/abdomen/pe
lvis), or PET-CT 
XI 
 
 
 
 
 
 
 
 
 
 
 
X 
 
QOL Assessment, 
FACT-Cx  
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Assess for 
MDS/AMLJ 
 
X 
 
 
 
 
 
 
 
X 
 
X 
X 
XN 
DLT Assessment 
 
 
 
 
 
 
 
 
XO 
 
 
 
 
 
CORRELATIVE STUDIES 
PARP testingK  
 
X 
X 
 
X 
 
 
 
 
 
 
 
 
 
Bone marrow 
aspirate and biopsy 
if neededL  
 
X  
 
TREATMENT 
Niraparib  
 
Continuous, DailyP  
 
 
 
Radiotherapy 
 
X 
X 
X 
X 
X 
X 
X 
 
 
(A) Allowed windows are based upon frequency of the assessment, as follows.  Weekly assessments: +/- 3 days; 28-day 
assessments: +/- 7 days; Q3-month assessments: +/- 14 days.   
(B) Medical History should include all prior anticancer therapy.   
(C) After completing radiotherapy, subject may continue on niraparib per Section 4.1.  Drug is administered in 28-day cycles, and 
may continue until the criteria in Section 4.1 is met to discontinue treatment.  
(D) After stopping niraparib, subjects will have an End of Treatment visit within 28 days of stopping study drug.  
(E) After stopping niraparib, patients will be followed every 3 months for 1 year after stopping niraparib. Post-niraparib visits: 3, 6, 
9 and 12 months.   
(F) Must include: bilirubin, AST, ALT, serum creatinine, sodium, potassium, chloride, CO2, blood urea nitrogen (BUN), glucose.  
At pre-study, bilirubin is required for eligibility. See Section 3.   
(G) Female subjects of childbearing potential as defined in the eligibility criteria must have a serum pregnancy test within 14 days 
of registration.  Pregnancy test must be repeated ≤ 7 days prior to CT simulation if more than 14 days has elapsed since the 
last pregnancy test. 
(H) Physician will use NCI CTCAE scale. AEs will be graded and recorded.   
(I) Baseline imaging must be within 56 days of registration.     
(J) MDS/AML follow-up:  Chart review to evaluate for MDS or AML diagnosis.  


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(K) Peripheral blood mononuclear cells will be collected for PARP testing on Days 1, 8, and 22.  See Section 7. 
(L) For any patient suspected for MDS/AML while on study, assessments should be conducted as per standard clinical care, 
such as bone marrow aspirate/biopsy.  A copy of the hematologist's report of aspirate/biopsy findings including a classification 
according to WHO criteria and other sample testing results related to MDS/AML will be communicated to Tesaro, if applicable. 
(M) At minimum, the Performance Status must be assessed by the investigator every 3 months during maintenance. 
(N) Chart review should be conducted every 12 months (+/- 2 months) for five years after the completion of radiotherapy. 
(O) DLT assessment is not a subject visit, but a study evaluation point.  DLT assessment will occur for all subjects upon 
completion of concurrent radiation therapy and niraparib administration.  Study staff will use the outcome of DLT assessment 
to determine dose level determination for subsequent study enrollment.  
(P) Niraparib administration will be given continuously on 28-day cycles, except during HDR brachytherapy when niraparib dosing 
is held. 
(Q) During Maintenance, pelvic exam is only required every 3 months.       
 
 
 
 
 
 


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10 ADVERSE EVENT REPORTING 
 Definition of Adverse Events 
Any untoward medical occurrence in a patient or clinical investigation subject 
administered a medicinal product and which does not necessarily have to have a 
causal relationship with this treatment. An AE can therefore be any unfavorable and 
unintended sign (including a clinically significant abnormal laboratory finding, for 
example), symptom, or disease temporally associated with the use of study 
treatment, whether or not considered related to the study treatment.  
AEs may include the onset of new illness and the exacerbation of pre-existing 
medical conditions. An AE can include an undesirable medical condition occurring at 
any time after the time of randomization and/or treatment assignment, including 
baseline or washout periods, even if no study treatment has been administered. 
The term “unexpected” refers to an event or reaction that is not listed in the current 
investigator’s brochure or approved Informed Consent Form as a possible risk or 
discomfort or is not listed at the specificity or severity that has been observed. 
 Serious Adverse Events (SAEs) 
Any untoward medical occurrence that, at any dose; 
 Results in death;  
 Is life threatening (i.e., an event in which the patient was at risk of death at the 
time of the event; it does not refer to an event that hypothetically might have 
caused death if it were more severe);  
 Requires inpatient hospitalization* or prolongation of existing hospitalization;  
 Results in persistent or significant disability/incapacity;  
 Is a congenital anomaly/birth defect; or 
 Is an important medical event** 
 
*Exception: Preplanned (at time of informed consent) hospitalization for elective 
procedures, for protocol compliance or social reasons, or for observation will not be 
considered criteria for an SAE. The reason for the planned hospitalization should be 
documented. Complications experienced during these hospitalizations must be 
reported as SAEs if hospitalization is prolonged due to AE, or if the complication 
meets other serious criteria). 
 
**Medical and scientific judgment should be exercised in determining whether 
situations or events should be considered serious adverse events:  an important 
medical event may not be immediately life-threatening or result in death or require 
hospitalization but may jeopardize the patient or require intervention to prevent one 
of the above outcomes.  Examples of such events are allergic bronchospasm, blood 
dyscrasias, or convulsions that may require intensive treatment in an emergency 
room or at home but do not result in hospitalization, development of drug 


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dependency or drug abuse, and transmission of disease associated with the 
administration of the study drug.  
 Adverse Events of Special Interest 
An Adverse Events of Special Interest is defined as any AE (serious or non-serious) 
that is of scientific and medical concern specific to the study treatment, for which 
ongoing monitoring and rapid communication by the Investigator to the Sponsor-
Investigator and TESARO is required.  
Adverse Events of Special Interest (AESI) for niraparib include the following:  
 Myelodysplastic Syndromes (MDS) and Acute Myeloid Leukemia (AML) 
 Secondary cancers (new malignancies [other than MDS or AML]) 
 Pneumonitis 
 Embyro-fetal toxicity 
 
AESI should be collected and reported as follows: 
 MDS and AML along with other secondary cancers should be reported to the 
PI and TESARO upon awareness for any patient who has received niraparib 
(regardless of the timeframe since the last dose). 
 Pneumonitis should be reported to the Sponsor-Investigator and TESARO 
through 90 days after the last dose of niraparib. 
 Embryo-fetal toxicity should be reported as outlined in the Pregnancy 
reporting section. 
 Special Situations: Abuse, Misuse, Medication Errors, Overdose, and 
Accidental or Occupational Exposure 
 Abuse:  is the persistent or sporadic, intentional excessive use of the study 
treatment which is accompanied by harmful physical or psychological effects.  
 Misuse: medicinal product is intentionally and inappropriately used not in 
accordance with the authorized/approved product information. 
 Medication error:  is any preventable incident that may cause or lead to 
inappropriate study treatment use or patient harm while the study treatment is 
in the control of the health care professionals or patients. Such incident may 
be due to health care professional practice, product labeling, packaging and 
preparation, procedures for administration, and systems, including the 
following: prescribing, order communication, nomenclature, compounding, 
dispensing, distribution, administration, education, monitoring, and use. 
 Overdose:  is a deliberate or accidental administration of study treatment to a 
study patient, at a dose greater than that which was assigned to that patient 
per the study protocol and under the direction of the Investigator.  If an 


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overdose occurs with a TESARO product, the Sponsor-Investigator and 
TESARO should be notified immediately, and the patient should be observed 
closely for AEs. Associated AEs should be treated and monitored by the 
Investigator. The dosage of study drug administered, any associated AEs, 
and/or treatment provided to the patient because of the overdose, should be 
reported.  
 Accidental /Occupational exposure:  is the unintentional exposure to a 
study treatment as a result of one’s professional or non-professional 
occupation, or accidental exposure to a non-professional to whom exposure 
was not intended (i.e., study product given to wrong patient).  
 Reporting Special Situations:   
All occurrences of abuse, misuse, medication error, overdose, and accidental 
or occupational exposure associated with a TESARO product must be 
reported on an SAE Report Form to the Sponsor-Investigator and to TESARO 
within 5 business days of awareness regardless of whether or not an AE or 
SAE has occurred.  If the abuse, misuse, medication error, overdose, or 
accidental / occupational exposure is associated with an AE, an SAE Report 
Form must also be submitted to the Sponsor-Investigator and to TESARO 
within 24 hours of awareness. 
 Assessment of Adverse Events 
Each AE will be assessed by the investigator with regard to severity and causality 
with regard to study treatment as outlined below. 
10.5.1 
Severity Assessment 
All AEs will be assessed by the Investigator for severity* according to Common 
Terminology Criteria for Adverse Events (CTCAE) v4.03: 14 June 2010; National 
Institutes of Health (NIH), National Cancer Institute (NCI). The CTCAE severity 
grades 1 through 5 provide unique clinical descriptions of severity of each adverse 
event. The CTCAE v4.03 is available on the NCI/NIH website. 
Please note that there is a distinction between serious and severe AEs: Severity is 
a measure of intensity whereas seriousness is defined by the criteria in Section 10.1.  
For example, a mild degree of gastrointestinal bleeding requiring an overnight 
hospitalization for monitoring purposes may be considered an SAE but is not 
necessarily severe.  
10.5.2 
Relationship to Study Drug 
The Investigator must provide a causality assessment regarding the relationship of 
the event with the study drug and/or study procedure for all AEs.  One of the 


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following categories should be selected based on medical judgment, considering all 
contributing factors: 
 Related: The AE is clearly related to the study treatment/medicinal product. 
 Probably Related: The AE is likely related to the study treatment/medicinal 
product. 
 Possibly Related: The AE may be related to the study treatment/medicinal 
product. 
 Not Likely Related: The AE is doubtfully related to the study 
treatment/medicinal product.    
 Not Related: The AE is clearly NOT related to the study treatment/medicinal 
product.  
 Collection and Recording of Adverse Events 
AEs may be volunteered spontaneously by the study patient, or discovered by the 
study staff during physical examinations or by asking an open ended question such 
as, “How have you been feeling since your last study visit?” The Investigator or 
designee will document the nature of AE, date of onset of the AE (and time, if 
known), date of outcome of the AE (and time, if known), severity of the AE, action 
taken with study drug as a result of the AE, assessment of the seriousness of the 
AE, and assessment of the causal relationship of the AE to study drug and/or study 
procedure. 
AEs, including laboratory abnormalities that are assessed as clinically significant or 
require intervention, should be described using a diagnosis whenever possible, 
rather than individual underlying signs and symptoms. When a clear diagnosis 
cannot be identified, each sign or symptom should be recorded as a separate AE. 
All SAEs will be collected from the start of treatment for this study through 30 days 
post treatment and reported accordingly. SAEs considered by the Investigator to be 
related to study medication are reported throughout the Follow-up Assessment 
Period. 
 All AEs, regardless of the source of identification (e.g., physical examination, 
laboratory assessment, or reported by patient), will be documented for each patient 
from the time of treatment assignment through the final follow-up visit. 
Concomitant illnesses that existed before entry into the study will not be considered 
AEs unless the illness worsens during the Treatment Period. Pre-existing conditions 
will be recorded as Medical History. 
Disease progression is an efficacy criterion and is therefore not considered an AE or 
SAE (even if fatal). Disease progression should be documented. If AEs/SAEs occur 
in relation to disease progression that are not consistent with the natural progression 
of the patient’s disease, these AEs/SAEs must be reported per AE/SAE reporting 
requirements. 


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 Follow-Up of Adverse Events 
All AEs experienced by a patient, regardless of the suspected causality, will be 
monitored until the AE or SAE has resolved, until any abnormal laboratory values 
have returned to baseline or normal levels, until stabilized with a satisfactory 
explanation for the changes observed, until the patient is lost to follow-up, or until the 
patient has died. 
 Reporting to the Sponsor-Investigator 
All SAEs and AESIs must be reported to the Sponsor-Investigator within 24 hours of 
becoming aware of the initial SAE/AESI or any follow-up information regarding the 
SAE/AESI using the SAE reporting information below.  SAEs/AESIs must be 
reported after study completion, if the SAE/AESI is assessed as study-drug related. 
 
Sponsor-Investigator SAE, AESI Reporting Information 
Michelle S. Ludwig, MD, MPH, PhD 
 Email: Michelle.Ludwig@bcm.edu 
Telephone: (713) 566-3757 
 Reporting to TESARO 
The Sponsor-Investigator must report all SAEs and all follow up information to 
TESARO on an SAE Report Form within 24 hours of becoming aware of the initial 
event or follow-up information.  
The Sponsor-Investigator must provide a causality assessment and must sign and 
date all SAE Report Forms. 
If supporting documentation is included in the submission to TESARO (e.g., hospital 
reports, consultant reports, death certificates, autopsy reports, etc.), please redact 
any patient identifiers (including Medical Record number). 
 
TESARO SAE, Pregnancy, and AESI Reporting Information 
Email: OAX37649@gsk.com 
Fax: +44(0) 208754 7822 
 
On a monthly basis, the Sponsor-Investigator will provide TESARO with a line listing 
of all SAEs/AESIs that have been reported to date.  On at least an annual basis, the 
Sponsor-Investigator will provide a copy of the safety reports submitted to applicable 


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Regulatory Authorities or IECs.  Annual reports should be provided to TESARO 
within 3 business days of submission to the applicable regulatory body. 
TESARO’s practice is to acknowledge receipt of all safety information within 72 
hours.  The Sponsor-Investigator should resend any materials that are not 
acknowledged within this time period. 
 
Quarterly AE/SAE Reporting to TESARO 
On a quarterly basis the Sponsor-Investigator will provide TESARO with a line listing 
of all adverse events (serious and non-serious) received during a defined quarter. 
The line listing will include a subject ID, the AE term, onset date, outcome, causality 
assessment, severity, and study drug dosing information.    
 
Pregnancy 
The Sponsor-Investigator has the responsibility to monitor the outcome of all 
pregnancies reported during the Investigator Sponsored Trial. 
The Sponsor-Investigator must report all pregnancies associated with TESARO 
product including follow up outcomes to TESARO within 24 hours of awareness.  
Each pregnancy must be reported on a Pregnancy Notification Form within 24 hours 
of becoming aware of the pregnancy. Pregnancy is not an AE, and therefore does 
not need to be reported as an AE unless there is a suspicion that the study drug may 
have interfered with the effectiveness of a contraceptive medication.  
An elective abortion without complications should not be regarded as an AE, 
however, it should be reported as the outcome to the pregnancy on the Pregnancy 
Outcome Report Form. Therapeutic abortions should be reported as a treatment 
procedure; the reason for the therapeutic abortion should be reported on the 
Pregnancy Outcome Report Form and as an AE. Hospitalization for normal delivery 
of a healthy newborn should not be considered an SAE. 
Any SAE that occurs during pregnancy must be recorded on the Pregnancy 
Outcome Report Form, reported as an SAE on the SAE Report Form (e.g., maternal 
serious complications, therapeutic abortion, ectopic pregnancy, stillbirth, neonatal 
death, congenital anomaly, birth defect) and reported to the Sponsor-Investigator 
and TESARO within 24 hours. Hospitalization for normal delivery of a healthy 
newborn should not be considered an SAE.  
 
Suspected Unexpected Serious Adverse Reactions (SUSARs) 
Per regulatory requirements, if an event is assessed by the Sponsor-Investigator as 
a Serious Unexpected Suspected Adverse Reaction (SUSAR), it is the responsibility 
of the Sponsor-Investigator to submit the SUSAR to the appropriate Regulatory 
Authorities according to applicable regulations, as outlined in the following sections. 


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10.12.1 Reporting of SUSARs to the FDA 
Serious adverse events that are determined by the sponsor to be a SUSAR will be 
reported to the FDA as an IND Safety Report within 15 calendar days of sponsor’s 
awareness of the event.   
Unexpected fatal or life-threatening suspected adverse events will be reported to the 
FDA as an IND Safety Report within 7 calendar days of sponsor’s awareness of the 
event. 
Follow up information pertaining to a previously submitted IND Safety Report will be 
submitted as soon as available and no later than 15 calendar days after sponsor’s 
awareness of the information. 
These reports will be submitted using Form 3500A. 
10.12.2 Reporting to IRB 
Adverse events will be reported to the Institutional Review Board (BCM IRB) according 
to their reporting requirements and required time frame. 
 
Any event that is reportable to the BCM IRB must also be reported to the DLDCCC 
Data Review Committee (DRC) via the Patient Safety Officer at dldcc-pso@bcm.edu.   
 
 
Reporting Product Complaints for Niraparib 
Any written, electronic or oral communication that alleges dissatisfaction related to 
manufactured clinical drug product with regards to its manufacturing, testing, 
labeling, packaging, or shipping, must be reported by the sponsor-investigator or 
qualified designee to TESARO QA at TESARO.QA@gsk.com.  The product and 
packaging components in question, if available, must be stored in a secure area 
under specified storage conditions until it is determined whether the product is 
required to be returned for investigation of the defect.  If the product complaint is 
associated with an SAE, the SAE must be reported separately in accordance with 
the protocol, and the SAE report should mention the product quality complaint. 


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11 DATA REPORTING 
 Data submission 
All subject data will be abstracted from the electronic medical record available for 
each enrolled patient and documented in an electronic database created for this 
study using OnCore, the proprietary, HIPAA-compliant software used by Baylor 
College of Medicine for these purposes. The specific demographic data to be 
abstracted are specified in Section 6.2. Each subject will be assigned a study code 
to facilitate subsequent coding of the data set once complete. This number will be 
used to link any primary source data stored in the HIPAA-compliant electronic 
database used for this study.  
 Data and Safety Monitoring 
This study will be reviewed regularly by the Data Review Committee (DRC) of the 
Dan L. Duncan Comprehensive Cancer Center.  The DRC will monitor the study for 
progress and enrollment, toxicities, adverse events, and soundness of data. 
 
The frequency of data review by the DRC is determined by the Protocol Review and 
Monitoring Committee at the time of initial review and is based on the level of risk to 
the study subjects.  Review will occur at a minimum of once each year after 
activation.  Information reviewed by the committee includes: 
a. Overall protocol accrual and expected number of patients to be treated 
b. Patient registrations with regard to eligibility and evaluability 
c. All adverse events and their relationship to the protocol therapy (e.g. 
by dose level, treatment arm, etc.) in order to determine if participants 
are being exposed to unanticipated or excessive toxicity 
d. All serious adverse events or unanticipated problems requiring 
expedited reporting as defined in the protocol 
e. Results of any planned interim analyses 
f. Response evaluations, if relevant 
g. Any issues with protocol conduct or compliance 
h. Status of participation rate in correlative biology and/or imaging 
studies, if applicable 
i. Study amendments or modifications that may have occurred since last 
review 
j. Date of next planned review 
 Audits  
All study documents (both source and abstracted) will be made available for 
inspection by and/or other relevant state and/or federal regulatory authorities as 
applicable with 48 hours of advance notice. The principal investigators, co-
investigator and study personnel will also make themselves available upon 48 hour 
notice at the request of TESARO and/or any relevant institutional state and/or 
federal authorities.  


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 Data Quality Assurance 
This study will be monitored by the DLDCCC Quality Assurance program for study 
conduct and quality of data, according to CTSU policy.  Protocol compliance, 
eligibility verification, informed consent procedure verification, and data accuracy will 
be monitored. 
 


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12 STATISTICAL METHODS 
 Study Design and Endpoints  
This is a single arm combination Phase I/II trial of niraparib to evaluate the safety 
and efficacy of niraparib administered concurrently with whole pelvic radiation for 
patients who present with metastatic cervical cancer. Design ensures enrollment of 
the required number of patients for efficacy endpoint (phase II component), while 
continuously monitoring safety, ensuring correct selection of the MTD and allocation 
of maximum number of patients to the MTD group (phase I component)    
 Primary Endpoint 
The primary endpoint of the Phase I component is to determine the MTD of niraparib 
when given concurrently with pelvic radiotherapy.   
 
The primary endpoint of the Phase II component is defined as 12 month pelvic 
(local) control for patients who have received 1 or more doses of niraparib with 
pelvic radiation as part of their treatment for a metastatic cervical cancer.  
 
Progression event will be defined as local (pelvic) disease progression as 
determined by the investigator, and may be clinical, radiological, or pathological. If 
the patient receives subsequent oncologic therapy, then the date of failure will be 
their visit prior to initiating therapy. Patients with no event (e.g. disease free) will be 
censored at the time of last contact. Local progression-free survival is measured 
from the time of treatment initiation to progression. 
 
Recurrence will be determined as the time from baseline CT or PET-CT date to 
pathologic or radiologic diagnosis of any local or distant disease, receipt of any 
additional anti-cancer therapy, or death from any cause.  Response and progression 
will be evaluated in this study using the new international criteria proposed by the 
Response Evaluation Criteria in Solid Tumors (RECIST) Committee (version 1.1).  
Changes in only the largest diameter (unidimensional measurement) of the tumor 
lesions are used in the RECIST criteria. 
 Secondary Endpoints 
1: Assess the acute toxicity profile of niraparib administered concurrently with 
whole pelvic radiotherapy according to the CTCAE version 4 as well as the 
grade of each toxicity. 
 
2: Assess quality of life for women receiving niraparib concurrently with whole 
pelvic radiotherapy.  
 
3: Assess tumor response outside the radiation field using RECIST 1.1 for 
women receiving niraparib concurrently with whole pelvic radiotherapy.  


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 Sample size, Accrual Rate and Study Duration 
This study will be conducted using a Bayesian Optimal Interval (BOIN) design with a 
target DLT rate of 0.3 (Table 2). This design has algorithmic escalation/de-escalation 
rules easy to implement like a traditional 3+3 design but allows for specification of 
the target DLT rate, different size cohorts, is more likely to correctly select the MTD 
and allocate more patients to the MTD (see simulation results in Table 7) and 
expands consistent toxicity monitoring to the entire cohort. Calculations were done 
using R package BOIN (version 2.4, 2016 May 11, available from https://cran.r-
project.org/web/packages/BOIN/index.html) 
 
 Phase I component considerations. 
The study is designed to escalate the dose if the observed toxicity rate at the current 
dose is <= 0.2365, and de-escalate the dose if the observed toxicity rate at the 
current dose is >= 0.3585. If the observed toxicity rate is between 0.2365 and 
0.3585, additional patients will be treated at the current dose. For cohorts of size 3, 
the decision boundaries are shown in Two doses levels of niraparib (100mg and 200 
mg) will be evaluated for use with concurrent pelvic radiotherapy. Study will begin at 
dose 100mg and escalate / de-escalate according to study design rules described.  
 
 
 


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Table 7: Simulations for study design justifications 
 
 
Scenarios 
 
Dose 
 
True 
DLT 
Rate 
BOIN (Phase I/II) 
Phase I "3+3" 
Phase I "3+3" + Phase II 
Fraction 
Treated 
MTD 
selected 
average 
# of 
patients 
Fraction 
Treated 
MTD 
selected 
Fraction 
Treated# 
% 
evaluated 
for safety 
average 
# of 
patients 
1.  
Very safe 
<100mg 
  
  
0.0% 
21.8  
  
2.8% 
  
  
22.8  
100mg 0.05 
0.18 
0.8% 
0.51 
18.0% 
0.17 
  
200mg 0.15 
0.82 
99.2% 
0.49 
79.2% 
0.83 
20.3% 
2. 
Intermediate 
safe 
<100mg 
  
  
1.1% 
23.4  
  
20.1% 
  
  
23.2  
100mg 0.15 
0.33 
16.6% 
0.61 
31.1% 
0.22 
  
200mg 0.25 
0.69 
82.3% 
0.39 
48.8% 
0.78 
13.8% 
3.  
Safe at low 
doses only 
<100mg 
  
  
3.6% 
24.0  
  
33.5% 
  
  
21.3  
100mg 
0.2 
0.64 
77.0% 
0.71 
54.3% 
0.88 
27.6% 
200mg 
0.5 
0.36 
19.4% 
0.30 
12.2% 
0.12 
  
4.  
Unsafe 
<100mg 
  
  
89.3% 
8.9* 
  
95.7% 
  
*  
4.3* 
100mg 
0.6 
0.96 
10.7% 
0.97 
4.0% 
  
  
200mg 
0.7 
0.04 
0.0% 
0.03 
0.3% 
  
  
* stopped early for safety                  # If MTD chosen correctly 


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 Phase II component considerations. 
The cohort treated at the MTD will enroll patients to the total of 17 patients needed 
for the evaluation of improvement in time to local progression-free survival. We have 
comprehensively reviewed local control outcomes for all women treated for a 
locoregionally advanced cervical cancer (bulky FIGO III- IVA) with 
chemoradiotherapy to include standard of care concurrent cisplatin at the Harris 
Health System between April, 2008 and April, 2015. Twelve month local 
progression-free survival for patients who presented with FIGO IIIA-IVA cervical 
cancer who receive less than the 6 cycles of standard of care concurrent cisplatin is 
52%. Since this clinical trial is in a more advanced stage of population, we estimate 
that the local control would be 50% with standard of care and we will consider the 
trial a success if it is better than a 70% at 12 months. The criterion for significance 
(alpha) has been set at 0.10.  The test is 1-tailed, which means that an effect in one 
direction (improvement) is expected and will be interpreted. Calculation are based 
on the assumptions of uniform accrual over time, exponentially distributed death 
times, and use of the exponential MLE test. With the proposed sample size of 17 
patients, accrued over 2 years and followed for at least 1 year, the study will have 
power of 80% to yield a statistically significant result.  
 
Total study sample size. 
This study will enroll at least 3 patients at each dose level and at least 17 patients at 
the MTD level. Participants will continue to be enrolled and monitored for toxicity 
according to the rules specified above until 17 efficacy evaluable participants have 
been enrolled to any single dose level. For the purposes of this analysis, a subject is 
considered evaluable for the primary endpoint after completing at least one dose of 
niraparib. It is expected that all dose levels will be safe and assuming that even the 
highest dose level has a DLT rate substantially lower than the target (i.e. <10%), 
which is what we expect, we will have more than 99% chance of selecting the top 
dose level at the end of the trial. In this case the total number of patients enrolled 
would be 20 (3+17). Simulations of other scenarios are shown in Table 7.  The 
maximum number that will be needed would be 24. 
 
Adjusting for missing data 
When evaluating our data from the past 6 years, we found that none of the patents 
were lost to follow-up, so a conservative adjustment of less than 10% (i.e. additional 
2 patients) is used for the total of up to 22-27 patients.  All efforts will be made via 
chart review to obtain information regarding missing data. 
 
 
 
 


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Accrual Rate 
 
Given the large number of women with metastatic advanced cervical cancer treated 
at our center, we anticipate that we should be able to accrue 10 patients per year.  
As such, accrual to take no longer than 2 years with planned study completion within 
an upper limit no longer than 3 years. 
Stratification Factors 
Not applicable 
Interim Monitoring Plan 
The BOIN design requires continued toxicity monitoring. No interim data analyses 
are planned for efficacy endpoint. 
Analysis of Primary Endpoints 
The primary objective of the Phase I component is to determine the MTD based on 
DLT (as described previously) of niraparib when given concurrently with pelvic 
radiotherapy.  The dose enrolling required 17 patients according to rules described 
in Table 2 will be determined to be the MTD. The posterior DLT rate and 95% 
confidence interval will be estimated using all toxicity evaluable cases. 
 
For the efficacy analysis, we evaluate the effectiveness of concurrent niraparib by 
measuring local progression free survival using the exponential MLE test at 
alpha=0.05 level. Descriptive and summary statistics will be computed for 
demographic and clinical data of all subjects enrolled in the study. A Kaplan-Meier 
plot will be constructed to illustrate the progression-free survival trends observed. 
Analysis of Secondary Endpoints 
Toxicity will be reported as the frequency of each toxicity according to the CTCAE 
version 4.0 as well as the grade of each toxicity. Overall survival will be analyzed by 
Kaplan-Meier method.  The associations between biological measurements and 
recurrence-free survival will be analyzed by the Cox regression. Quality of life will be 
used to determine the prevalence and duration of acute and long-term symptoms 
and symptom scores using FACT-Cx. FACT-Cx is used as the quality of life 
measure as this is our current departmental standard for all cervical cancer patients 
and there is no cost to use the instrument.  The FACT Cx is commonly used in 
GOG/NRG studies.  The tumor response rate (and corresponding confidence 
intervals) outside of the radiation field will be reported using RECIST 1.1. All of these 
analyses will be considered exploratory in nature. 


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13 ETHICAL, LEGAL, AND ADMINISTRATIVE ASPECTS 
 Good Clinical Practice 
This study will be conducted according to the principles of respect for persons, 
beneficence, and justice as stated in the Belmont Report.  This study will also 
embrace the principles set forth in the Declaration of Helsinki.  Investigators will 
comply with the provisions for the protection of the rights and welfare of human 
research subjects set forth in the U.S. Code of Federal Regulations, Title 45 Part 46, 
and in compliance with determinations of all Institutional Review Boards (IRBs) 
overseeing the research.  All institutions participating in the protocol will have in 
place a Federal Wide Assurance (FWA) with the DHHS Office of Human Subjects 
Research Protections. This assurance documents the institution’s commitment to the 
human subjects regulations.  
 
The study will also be conducted under Good Clinical Practice (GCP) as laid out in 
the International Conference on Harmonisation (ICH) E6 GCP Consolidated 
Guidance (ICH 1996).  Investigator responsibilities are set out in Section 4 of the E6 
Guideline (as published in the Federal Register May 1997). Sponsor responsibilities 
are set out in Section 5 of the E6 ICH Guideline (as published in the Federal 
Register May 1997).  
 Informed Consent 
The informed consent document will be reviewed and approved by the IRB 
responsible for protecting the safety and welfare of subjects participating in 
research.  Informed consent will be obtained from research participants by the PI or 
other staff with appropriate training and documentation of task delegation.  
 Protocol Approval and Amendment 
The principal investigator will obtain permission from the local Institutional Review 
Board and/or all other regulatory or monitoring committees required to initiate study 
activities prior to subject enrollment. Study amendments will be propagated by 
submission first to TESARO, Inc. Once approved, amendments will be submitted in 
a timely fashion to IRB, FDA and/or all other regulatory committees for evaluation 
and approval prior to modifying study conduct. No modifications to the study protocol 
will be allowed without TESARO approval and/or subsequent approval of applicable 
IRBs.   
 Investigator Responsibilities 
The investigator is responsible for conducting studies in accordance with the 
protocol.  The investigator will ensure that there is adequate training for all staff 
participating in the conduct of the study and will supervise study tasks performed by 
the staff.  The investigator is also responsible for protecting the rights, safety and 
welfare of subjects under their care.   
 


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 Subject Confidentiality and Data Protection 
Confidentiality of all protected health information will be strictly maintained for all 
subjects enrolled in this protocol. The HIPAA-compliant electronic database used to 
abstract demographics, laboratory values and/or all other clinical data required by 
this protocol is maintained on a limited-access, password protected server 
maintained by BCM and/or BCM affiliates (HIPAA-compliant covered entities) 
specifically for this purpose. Access to this database as well as the server requires 
the use of Citrix-supported software designated for this purpose. Furthermore, 
access to the server and database require active passwords issues by Baylor 
College of Medicine for this purpose. Copies of any written documentation 
containing PHI will be maintained within locked file cabinets within the Dan L. 
Duncan Comprehensive Cancer Center. Access to the areas where these file 
cabinets are stored requires photo identification, which is routinely verified by BCM 
Security upon entering the campus.  
 Access to Source Documents 
Source documentation will be maintained according to standard practice within the 
Clinical Trials Support Unit at the Dan L. Duncan Comprehensive Cancer Center. 
Access to support documentation maintained within the CTSU will be provided to 
appropriate state, federal or local authorities as required by law. In addition, access 
to source documentation will be provided to the study collaborator (Tesaro, Inc.) as 
requested, in accordance with HIPAA and all other appropriate institutional policies 
and procedures. 
 Archival 
Study records will be maintained securely for a minimum of at least 3 years as per 
relevant institutional, state and federal requirements.  
 Publications  
Study investigators reserve the right to communicate and publish study outcomes. 
To this end, the principal investigator will be responsible for the preparation and 
submission of all abstracts, presentations and manuscripts summarizing study 
outcomes, in collaboration with other study investigators.  
 
 


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14 REFERENCES 
1. 
Fong PC, Boss DS, Yap TA, et al. Inhibition of poly(ADP-ribose) polymerase 
in tumors from BRCA mutation carriers. N Engl J Med. 2009; 361(2):123-134. 
2. 
De Lorenzo SB, Patel AG, Hurley RM, Kaufmann SH. The Elephant and the 
Blind Men: Making Sense of PARP Inhibitors in Homologous Recombination 
Deficient Tumor Cells. Front Oncol. 2013;3:228. 
3. 
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APPENDIX 1 – PERFORMANCE STATUS 
ECOG PS 
KARNOFSKY PS 
0—Fully active, able to carry on all pre-
disease performance without restriction 
100—Normal, no complaints; no 
evidence of disease 
90—Able to carry on normal activity; 
minor signs or symptoms of disease 
1—Restricted in physically strenuous 
activity but ambulatory and able to carry 
out work of a light or sedentary nature, 
e.g., light house work, office work 
80—Normal activity with effort, some 
signs or symptoms of disease 
70—Cares for self but unable to carry 
on normal activity or to do active work 
2—Ambulatory and capable of all self 
care but unable to carry out any work 
activities; up and about more than 50% 
of waking hours 
60—Requires occasional assistance but 
is able to care for most of personal 
needs 
50—Requires considerable assistance 
and frequent medical care 
3—Capable of only limited self care; 
confined to bed or chair more than 50% 
of waking hours 
40—Disabled; requires special care and 
assistance 
30—Severely disabled; hospitalization 
is indicated although death not 
imminent 
4—Completely disabled; cannot carry 
on any self care; totally confined to bed 
or chair 
20—Very ill; hospitalization and active 
supportive care necessary 
10—Moribund 
5—Dead 
0—Dead 
*Karnofsky D, Burchenal J, The clinical evaluation of chemotherapeutic agents in cancer. In: MacLeod C, ed. Evaluation of 
Chemotherapeutic Agents. New York, NY: Columbia University Press; 1949:191–205. 
**Zubrod C, et al. Appraisal of methods for the study of chemotherapy in man: Comparative therapeutic trial of nitrogen 
mustard and thiophosphoramide. Journal of Chronic Diseases; 1960:11:7-33. 
Available at: http://ecog-acrin.org/resources/ecog-performance-status 
 
  
 
 


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APPENDIX 2 –  RESPONSE CRITERIA 
Summary of the Response Evaluation Criteria In Solid Tumours (RECIST) 1.1 
A baseline scan is performed not more than one month before the start of treatment. 
Subsequent response to treatment is evaluated against this scan or the subsequent 
scan demonstrating the lowest sum of target disease (nadir). 
 
Target lesions are defined at baseline and must be ≥ 10 mm in longest diameter or ≥ 
15 mm in short axis if the lesion is a lymph node (although lymph nodes ≥ 10 mm 
are considered pathological, but non-measurable). If the CT slice thickness is > 5 
mm, the extranodal disease must be ≥ twice the slice thickness. Measurable disease 
on a chest radiograph is ≥ 20 mm, provided the lesion is "clearly defined and 
surrounded by aerated lung" (1). 
 
A maximum of 5 lesions may be chosen, with a maximum of 2 per organ. The sum 
of all the extra-nodal long axis measurements and nodal short axis measurements is 
calculated. When analysing a follow up scan, the same lesions are measured and 
the sum of target disease is again calculated. Measurements need not be along the 
same axis (as measured at baseline), but should always be the longest axis of the 
lesion at that point in time. It does not even have to be at the same slice position, 
provided the measurement is of the same lesion. However, if the initial 
measurements are in the axial plane, all further measurements of that lesion must 
remain in the axial plane. Likewise, if the initial measurements are in the coronal 
plane (this is acceptable), all further measurements of that lesion must be in the 
coronal plane. 
 
Bone lesions with a soft tissue component ≥ 10 mm can be designated as target 
lesions. Sclerotic bone lesions cannot be used. Although solid lesions should be 
used in preference, cystic lesions may be used provided they represent the disease 
being studied. 
 
If a lesion disappears, the measurement of that lesion is clearly 0 mm, however, if 
the lesion remains present, but is too small to measure accurately, a default 
measurement of 5 mm should be given. If lymph nodes decrease to < 10 mm, these 
are considered to be disease free, but remain target lesions (until new target lesions 
are selected - usually when disease has progressed and a new baseline scan is 
performed prior to a change in treatment). If lesions merge, the long axis of the 
resulting lesion is measured as one lesion in place of the individual lesions. If lesions 
split, the long axis of each individual lesion is added. 
 


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An increase of ≥ 20% from the nadir (or baseline, if it represents the point at which 
the sum of target disease was lowest) represents progressive disease. If the burden 
of non-target or non-measurable disease increases unequivocally, then progressive 
disease may be declared, but the increase really must be unequivocal. If a new 
lesion appears, progressive disease is declared. If, for example, there is doubt as to 
whether a lesion is new or, say, inflammatory change, follow up scans are required. 
If the new lesion is confirmed, the date of progression is taken to be the date on 
which the new lesion was first detected. 
 
A decrease in the sum of target disease of ≥ 30% represents partial response. 
Stable disease lies between partial response and progressive disease. 
Complete response is the disappearance of all lesions with nodes measuring < 10 
mm and normal tumour markers. 
 
If a lesion reappears after disappearing in a patient with complete response, 
progressive disease is declared. However, if such a lesion behaves in this manner in 
a patient with stable disease or partial response, it is the change in sum of target 
disease that defines the response or progression. 
PET-CT and MR may be used. The main specification is that imaging protocols are 
consistent throughout the trial. Therefore, contrast timings, MR sequences and 
planes should remain the same. 
 


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APPENDIX 3: QOL FORM (ENGLISH) 
FACT-Cx (Version 4) 
Below is a list of statements that other people with your illness have said are important. 
Please circle or mark one number per line to indicate your response as it applies 
to the past 7 days. 
 
 
 
PHYSICAL WELL-BEING 
 
Not 
at all 
A 
little 
bit 
Some
-what 
Quite 
a bit 
Very 
much 
 
GP1 
I have a lack of energy  
0 
1 
2 
3 
4 
GP2 
I have nausea  
0 
1 
2 
3 
4 
GP3 
Because of my physical condition, I have 
trouble meeting the needs of my family  
 
0 
 
1 
 
2 
 
3 
 
4 
GP4 
I have pain 
 
 
0 
1 
2 
3 
4 
GP5 
I am bothered by side effects of treatment  
0 
1 
2 
3 
4 
GP6 
I feel ill 
0 
1 
2 
3 
4 
GP7 
I am forced to spend time in bed 
 
 
0 
1 
2 
3 
4 
 
 
SOCIAL/FAMILY WELL-BEING 
 
Not 
at all 
A 
little 
bit 
Some
-what 
Quite
a bit 
Very 
much 
 
GS1 
I feel close to my friends  
0 
1 
2 
3 
4 
GS2 
I get emotional support from my family  
0 
1 
2 
3 
4 
GS3 
I get support from my friends  
0 
1 
2 
3 
4 
GS4 
My family has accepted my illness  
0 
1 
2 
3 
4 
GS5 
I am satisfied with family communication about 
my illness  
 
0 
 
1 
 
2 
 
3 
 
4 
GS6 
I feel close to my partner (or the person who is 
my main support)  
 
0 
 
1 
 
2 
 
3 
 
4 


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Q1 
Regardless of your current level of sexual 
activity, please answer the following question. If 
you prefer not to answer it, please mark this box  
and go to the next section. 
 
 
 
 
 
GS7 
I am satisfied with my sex life  
0 
1 
2 
3 
4 


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Please circle or mark one number per line to indicate your response as it applies 
to the past 7 days. 
 
 
 
EMOTIONAL WELL-BEING 
Not 
at all 
A 
little 
bit 
Some
-what 
Quite
a bit 
Very 
much 
 
GE1 
I feel sad  
0 
1 
2 
3 
4 
GE2 
I am satisfied with how I am coping with my 
illness  
0 
1 
2 
3 
4 
GE3 
I am losing hope in the fight against my illness  
0 
1 
2 
3 
4 
GE4 
I feel nervous  
0 
1 
2 
3 
4 
GE5 
I worry about dying  
0 
1 
2 
3 
4 
GE6 
I worry that my condition will get worse  
0 
1 
2 
3 
4 
 
 
 
 
FUNCTIONAL WELL-BEING 
 
Not 
at all 
A 
little 
bit 
Some
-what 
Quite
a bit 
Very 
much 
 
GF1 
I am able to work (include work at home)  
0 
1 
2 
3 
4 
GF2 
My work (include work at home) is fulfilling  
0 
1 
2 
3 
4 
GF3 
I am able to enjoy life  
0 
1 
2 
3 
4 
GF4 
I have accepted my illness  
0 
1 
2 
3 
4 
GF5 
I am sleeping well  
0 
1 
2 
3 
4 
GF6 
I am enjoying the things I usually do for fun  
0 
1 
2 
3 
4 
GF7 
I am content with the quality of my life right 
now  
0 
1 
2 
3 
4 
 
 
 


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Please circle or mark one number per line to indicate your response as it applies 
to the past 7 days. 
 
 
 
ADDITIONAL CONCERNS 
 
Not 
at all 
A 
little 
bit 
Some
-what 
Quite 
a bit 
Very 
much 
 
Cx1 
I am bothered by discharge or bleeding from 
my vagina  
0 
1 
2 
3 
4 
Cx2 
I am bothered by odor coming from my vagina  
0 
1 
2 
3 
4 
Cx3 
I am afraid to have sex  
0 
1 
2 
3 
4 
B4 
I feel sexually attractive  
0 
1 
2 
3 
4 
Cx4 
My vagina feels too narrow or short  
0 
1 
2 
3 
4 
BMT7 
I have concerns about my ability to have 
children  
0 
1 
2 
3 
4 
Cx5 
I am afraid the treatment may harm my body  
0 
1 
2 
3 
4 
BL4 
I am interested in sex  
0 
1 
2 
3 
4 
C7 
I like the appearance of my body  
0 
1 
2 
3 
4 
Cx6 
I am bothered by constipation  
0 
1 
2 
3 
4 
C6 
I have a good appetite  
0 
1 
2 
3 
4 
BL1 
I have trouble controlling my urine  
0 
1 
2 
3 
4 
BL3 
It burns when I urinate  
0 
1 
2 
3 
4 
Cx7 
I have discomfort when I urinate  
0 
1 
2 
3 
4 
HN1 
I am able to eat the foods that I like  
0 
1 
2 
3 
4 
 
 
 


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APPENDIX 4: QOL FORM (SPANISH) 
A continuación encontrará una lista de afirmaciones que otras personas con su misma enfermedad consideran 
importantes. Marque un solo número por línea para indicar la respuesta que corresponde a los últimos 7 días. 
 
ESTADO FÍSICO GENERAL DE SALUD 
 
Nada 
Un 
poco 
Algo 
Mucho 
Muchí- 
simo 
 
 
 
GP1 
    Me falta energía   
0 
1 
2 
3 
4 
 
GP2 
Tengo náuseas 
 
0 
1 
2 
3 
4 
 
GP3 
Debido a mi estado físico, tengo dificultad para atender a las 
necesidades de mi familia.  
 
 
0 
 
1 
 
2 
 
3 
 
4 
 
GP4 
Tengo dolor 
 
0 
1 
2 
3 
4 
 
GP5 
Me molestan los efectos secundarios del tratamiento 
 
0 
1 
2 
3 
4 
 
GP6 
    Me siento enfermo(a) 
 
0 
1 
2 
3 
4 
 
GP7 
    Tengo que pasar tiempo acostado(a) 
0 
1 
2 
3 
4 
 
 
AMBIENTE FAMILIAR Y SOCIAL  
Nada 
Un 
poco 
Algo 
Mucho 
Muchí- 
simo 
 
 
GS1 
Me siento cercano(a) a mis amistades 
 
0 
1 
2 
3 
4 
 
GS2 
Recibo apoyo emocional por parte de mi familia 
 
0 
1 
2 
3 
4 
 
GS3 
Recibo apoyo por parte de mis amistades 
 
0 
1 
2 
3 
4 
 
GS4 
Mi familia ha aceptado mi enfermedad 
 
0 
1 
2 
3 
4 
 
GS5 
Estoy satisfecho(a) con la manera en que se comunica mi 
familia acerca de mi enfermedad 
 
0 
 
1 
 
2 
 
3 
 
4 
 
GS6     Me siento cercano(a) a mi pareja (o a la persona que es mi        
principal fuente de apoyo) 
 
0 
 
1 
 
2 
 
3 
 
4 
 
 
Q1 
 
 
 
 
Sin importar su nivel actual de actividad sexual, conteste a la siguiente 
pregunta. Si prefiere no contestarla, marque esta casilla y continúe con la 
siguiente sección.      
 
     
  
     
 
 
     
 
 
GS7 
Estoy satisfecho(a) con mi vida sexual 
0 
1 
2 
3 
4 


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Marque un solo número por línea para indicar la respuesta que corresponde a los últimos 7 
días. 
 
 
ESTADO EMOCIONAL  
Nada 
Un 
poco 
Algo 
Mucho 
Muchí- 
simo 
 
 
GE1 
Me siento triste  
 
 
0 
1 
2 
3 
4 
 
GE2 
Estoy satisfecho(a) de cómo me estoy enfrentando a mi 
enfermedad 
 
 
0 
 
1 
 
2 
 
3 
 
4 
 
GE3 
Estoy perdiendo las esperanzas en la lucha contra mi  
enfermedad 
 
 
0 
 
1 
 
2 
 
3 
 
4 
 
GE4 
Me siento nervioso(a) 
 
0 
1 
2 
3 
4 
 
GE5 
Me preocupa morir 
 
0 
1 
2 
3 
4 
 
GE6 
Me preocupa que mi enfermedad empeore 
 
0 
1 
2 
3 
4 
 
 
CAPACIDAD DE FUNCIONAMIENTO PERSONAL  
Nada 
Un 
poco 
Algo 
Mucho 
Muchí- 
simo 
 
 
GF1 
Puedo trabajar (incluya el trabajo en el hogar) 
 
0 
1 
2 
3 
4 
 
GF2 
Mi trabajo me satisface (incluya el trabajo en el hogar) 
 
0 
1 
2 
3 
4 
 
GF3 
Puedo disfrutar de la vida 
 
0 
1 
2 
3 
4 
 
GF4 
He aceptado mi enfermedad 
 
0 
1 
2 
3 
4 
 
GF5 
Duermo bien 
 
0 
1 
2 
3 
4 
 
GF6     Disfruto con mis pasatiempos de siempre  
0 
1 
2 
3 
4 
 
GF7 
 
    Estoy satisfecho(a) con mi calidad de vida actual 
0 
1 
2 
3 
4 
 
 
 
 


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OTRAS PREOCUPACIONES 
Nada 
Un 
poco 
Algo 
Mucho 
Muchí- 
simo 
 
 
Cx1 
Me molesta el flujo o sangrado por la vagina 
 
0 
1 
2 
3 
4 
 
Cx2 
Tengo un olor vaginal que me molesta 
 
0 
1 
2 
3 
4 
 
Cx3 
Tengo miedo de tener relaciones sexuales 
 
0 
1 
2 
3 
4 
 
B4 
Me siento físicamente atractiva 
 
0 
1 
2 
3 
4 
 
Cx4 
Siento la vagina muy estrecha o pequeña 
0 
1 
2 
3 
4 
BMT7 Estoy preocupada por mi capacidad de tener hijos 
0 
1 
2 
3 
4 
 
Cx5 
 
Tengo miedo de que el tratamiento pueda hacerle daño a mi 
cuerpo 
0 
1 
2 
3 
4 
BL4 
Me interesa el sexo 
0 
1 
2 
3 
4 
 
C7 
Me gusta mi apariencia personal 
0 
1 
2 
3 
4 
Cx6 
Me molesta el estreñimiento 
0 
1 
2 
3 
4 
C6 
Tengo buen apetito 
0 
1 
2 
3 
4 
BL1 
Tengo dificultad para controlar la orina 
0 
1 
2 
3 
4 
BL3 
Siento ardor/escozor al orinar 
0 
1 
2 
3 
4 
Cx7 
Siento molestias al orinar 
0 
1 
2 
3 
4 
 
HN1 
Puedo comer lo que me gusta 
 
0 
1 
2 
3 
4 
 


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APPENDIX 5 – FIGO STAGING OF CANCER OF THE CERVIX 
UTERI (2018) 
Stage I 
The carcinoma is strictly confined to the cervix (extension to the uterine 
corpus should be disregarded) 
IA Invasive carcinoma that can be diagnosed only by microscopy, with 
maximum depth of invasion <5 mma 
IA1 Measured stromal invasion of <3.0 mm in depth  
IA2 Measured stromal invasion of ≥3.0 mm and <5.0 mm in depth 
IB Invasive carcinoma with measured deepest invasion ≥5 mm (greater than 
Stage IA), lesion limited to the cervix uterib 
IB1 Invasive carcinoma ≥5 mm depth of stromal invasion, and <2 cm in 
greatest dimension 
IB2 Invasive carcinoma ≥ 2 cm, and <4 cm in greatest dimension 
IB3 Invasive carcinoma ≥ 4 cm 
 
Stage II 
The carcinoma invades beyond the uterus, but has not extended to the lower 
third of the vagina or to the pelvic wall  
IIA Involvement limited to the upper two-thirds of the vagina without 
parametrial involvement 
IIA1 Invasive carcinoma <4.0 cm in greatest dimension 
IIA2 Invasive carcinoma ≥4.0 cm in greatest dimension 
IIB With parametrial involvement but not up to the pelvic wall 
Stage III 
The carcinoma involves the lower third of the vagina and/or extends to the 
pelvic wall and/or causes hydronephrosis or non-functioning kidney and/or 
involves pelvic or para-aortic lymph nodesc 
IIIA The carcinoma involves the lower third of the vagina, with no extension to 
the pelvic wall 
IIIB Extension to the pelvic wall and/or hydronephrosis or non-functioning 
kidney (unless known to be due to another cause) 
IIIC Involvement of pelvic and/or para-aortic lymph nodes, irrespective of 
tumor size and extent (with r and p notations)c 
 
IIIC1 Pelvic node metastasis only 
 
IIIC2 Para-aortic lymph node metastasis 
Stage IV 
The carcinoma has extended beyond the true pelvis or has involved (biopsy 
proven) the mucosa of the bladder or rectum. A bullous edema, as such, does 
not permit a case to be allotted to Stage IV  
IVA Spread of the growth to adjacent organs 
IVB Spread to distant organs (including peritoneal spread, involvement of 
supraclavicular, mediastinal, or paraaortic lymph nodes, lung, liver, or bone) 
 


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When in doubt the lower staging should be assigned. 
 
a. Imaging and pathology can be used, where available, to supplement 
clinical findings with respect to tumor size and extent, in all stages. 
b. The involvement of vasculat/lymphatic spaces does not change the 
staging.  The lateral extent of the lesion is no longer considered 
c. Adding notation of r (imaging) and p (pathology) to indicate findings that 
are used to allocate the case to Stage IIIC.  Example: if imaging indicates 
pelvic lymph node metastasis, the stage allocation would be Stage IIIC1r 
and if confirmed by pathologic findings, it would be Stage IIIC1p.  The type 
of imaging modality or pathology technique used should always be 
documented. 
 
 


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APPENDIX 6 – DRUGS WHICH ARE INHIBITORS OF P-
GLYCOPROTEINS (FROM FDA DRUG DEVELOPMENT AND DRUG 
INTERACTIONS) 
o Amiodarone (Cordarone®)  
o Azithromycin (Zithromax®)  
o Captopril (Capoten®)  
o Carvedilol (Coreg®)  
o Clarithromycin (Biaxin®)  
o Conivaptan (Vaprisol®)  
o Cyclosporine (Neoral®, Gengraf®, Sandimmune®)  
o Diltiazem (Cardizem®, Cartia®, Dilacor®, Diltia®)  
o Dronedarone (Multaq®)  
o Erythromycin (E.E.S®, Ery-tab®)  
o Felodipine (Plendil®)  
o Itraconazole (Sporanox®)  
o Ketoconazole (Nizoral®)  
o Lopinavir and ritonavir (Kaletra®)  
o Quercetin (supplement)  
o Quinidine  
o Ranolazine (Ranexa®)  
o Reserpine  
o Ritonavir (Norvir®)  
o Saquinavir (Invirase®)  
o Simeprevir (Olysio®)  
o Simvastatin (Zocor®)  
o Suvorexant (Belsomra®)  
o Tacrolimus (Prograf®)  
o Tamoxifen   
o Telaprevir (Incivek®)  
o Ticagrelor (Brilinta®)  
o Verapamil (Calan®,Covera-HS®, Isoptin®, Verelan®)  
 
 
 


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APPENDIX 7 – ACCEPTABLE CHEMOTHERAPY REGIMENS 
1. Cisplatin/paclitaxel/bevacizumab* 
2. Carboplatin/paclitaxel/bevacizumab* 
3. Cisplatin/paclitaxel 
4. Carboplatin/paclitaxel 
5. Cisplatin/topotecan 
6. Cisplatin 
7. Carboplatin 
 *If bevacizumab given, 6 weeks must elapse between last dose of 
bevacizumab and first radiation treatment.