Conditions: Breast Cancer Ovarian Cancer
Keywords: Breast Ovarian
Allocation: NON_RANDOMIZED | Intervention model: SINGLE_GROUP
Enrollment: 14
Healthy volunteers: no

Brief summary:
Open-label, cohort study to determine the feasibility and tolerability of the combination of daily niraparib and daily or thrice weekly everolimus for one 28-day cycle in patients with advanced ovarian and breast cancer.

Detailed description:
The goal of this study is to determine a maximum tolerated dose of the combination of niraparib and everolimus. To do this, investigators will estimate the maximum tolerated dose that is defined as the dose level at which less than one-third of patients will experience a dose-limiting toxicity. A traditional dose escalation design will be used, beginning with the lowest dose level and escalating to the maximum allowable dose level as specified in the protocol. One of the following outcomes will determine the treatment of subsequent patients:

* If none of the three patients experiences a dose-limiting toxicity , the next group of patients will be entered in the next higher dose cohort. All patients within a cohort must have completed at least one cycle (28 days) prior to initiation of the next cohort of patients.
* If one of the three patients experiences a dose-limiting toxicity , three more patients will be accrued at the current dose level. Subsequently, if only one of the six patients treated at this level experiences a dose-limiting toxicity , the dose will be escalated to the next higher dose in the next group of patients. If two or more of the six patients experiences a dose-limiting toxicity , the maximum tolerated dose has been exceeded and is defined as the previous dose at which no more than 1/3 experienced a dose-limiting toxicity .
* If at least two of the three experience a dose-limiting toxicity , the maximum tolerated dose has been exceeded and is defined as the previous dose at which no more than 1/3 experienced a dose-limiting toxicity .

If the lowest allowable dose level exceeds the maximum tolerated dose, the study will be terminated and the combination will not be deemed safe for use in this population. Additionally, the highest dose level will not be exceeded, even if no dose-limiting toxicities are experienced at that dose.

Investigators will summarize the adverse events overall and by individual adverse event categories. Serious adverse events will be summarized in a similar manner. These summaries will be performed overall and for each dose cohort. Investigators will summarize all events as well as the highest grade for a given subject. Investigators will summarize the number of subjects that exhibit a dose-limiting toxicity at each dose cohort and describe the dose-limiting toxicity for each subject, if applicable.

Arms:
arm 1: (each cycle is 28 days long) Everolimus 5mg daily on Mondays, Wednesdays, and Fridays Niraparib 100mg daily arm 2: (each cycle is 28 days long) Everolimus 5 mg daily on Mondays, Wednesdays, and Fridays Niraparib 200 mg daily arm 3: (each cycle is 28 days long) Everolimus 5 mg daily Niraparib 200 mg daily arm 4: (each cycle is 28 days long) Everolimus 5 mg daily Niraparib 300 mg daily

Interventions: intervention 1: niraparib intervention 2: everolimus
Intervention descriptions: intervention 1: Niraparib 100 mg will be administered orally once daily continuously. Niraparib will be administered as a flat-fixed dose (100mg, 200 mg, or 300 mg daily) depending on the cohort the patient is enrolled to, and not by body weight or body surface area. Each dose should be swallowed whole without chewing. The consumption of water is permissible. Patients should take doses at approximately the same times each day, and record this information in the patient diary. Patients will be provided with a diary in which to record their intake of study drug. However, the actual number of doses taken by the patient must be calculated from the number of tablets dispensed and returned. intervention 2: Everolimus 5 mg tablets will be used. Everolimus will be self-administered orally on a daily basis and doses will either be 5 mg (1 tablet) thrice weekly or 5 mg daily depending on the cohort the patient is enrolled to. Each cycle will be 28 days; everolimus will be taken continuously with no rest between cycles.

Protocol document:
Prot_SAP_000.pdf: 
NIRAPARIB 
CONFIDENTIAL & PROPRIETARY 
PROTOCOL [TNE001] Amendment 31-Aug-2020 
 
1 
A Phase 1 Evaluation of the Safety and Tolerability of Niraparib in 
Combination 
with 
Everolimus 
in 
Advanced 
Gynecologic 
Malignancies and Breast Cancer 
 
Sponsor: 
Avera Cancer Institute  
 
Principal Investigator: 
Dr. Casey Williams 
 
Sponsor Protocol Number: 
TNE001 
 
Study Drug Name: 
Niraparib 
 
Clinical Phase: 
1 
 
Number of Subjects: 
24 
 
IND Number:                                        134914 
 
 
EudraCT Number: 
 
Date of Original Protocol:                  25-Apr-2017 
 
Date of Current Protocol:                  31-Aug-2020 
 
Version:                                               Amendment 6 
 
 
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 
Avera 
Cancer 
Institute 
 
1000 East 23rd Street 
Sioux Falls SD 57105 
 
Principal Investigator  
Casey Williams, PharmD 
Avera Cancer Institute 
1000 E 23rd Street 
Sioux Falls SD 57105 
(605) 322-3588 
Casey.williams@avera.org 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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SPONSOR SIGNATURE PAGE 
 
Declaration of Sponsor or Responsible Medical Officer 
 
 
Title: A Phase 1 Evaluation of the Safety and Tolerability of Niraparib in 
Combination with Everolimus in Advanced Gynecologic Malignancies and 
Breast Cancer 
 
 
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. 
 
 
 
 
 
 
 
Casey Williams, PharmD 
Date 
Chief Scientific Officer 
 


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INVESTIGATOR SIGNATURE PAGE 
 
Declaration of the Investigator 
 
 
Title: A Phase 1 Evaluation of the Safety and Tolerability of Niraparib in 
Combination with Everolimus in Advanced Gynecologic Malignancies and 
Breast Cancer 
 
 
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 Harmonization (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 
 
 
 
 
 
 
 
Casey Williams, PharmD 
Date 
  Chief Scientific Officer


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TABLE OF CONTENTS 
Sponsor Signature Page ........................................................................................... 3 
Investigator Signature Page ..................................................................................... 4 
List of Abbreviations and Definitions ...................................................................... 8 
1 Introduction .......................................................................................................... 9 
1.1 
General Background ..................................................................................... 9 
1.2 
Ovarian Cancer ............................................................................................. 9 
1.3 
Breast Cancer ............................................................................................. 10 
1.4 
Background of PARP and PARP Inhibition ................................................. 11 
1.5 
Background on Homologous Recombination Deficiency (HRD) .................. 11 
1.6 
Background of Niraparib ............................................................................. 12 
1.6.1 Phase 1 Clinical Studies ......................................................................... 12 
1.6.2 Phase 3 Study (PR-30-5011-C) .............................................................. 12 
1.6.3 Baseline Platelet Count and Weight as Predictors of  
Thrombocytopenia .................................................................................. 13 
1.7 
PARP and mTOR inhibitors ........................................................................ 14 
1.8 
Rationale for Current Study ......................................................................... 15 
2 Overall Design and Plan of the Study .............................................................. 16 
2.1 
Overview ..................................................................................................... 16 
2.2 
Primary Objective ........................................................................................ 17 
2.3 
Secondary Objectives ................................................................................. 17 
2.4 
Exploratory Objectives ................................................................................ 17 
2.5 
Inclusion Criteria ......................................................................................... 18 
2.6 
Exclusion Criteria ........................................................................................ 19 
2.7 
Patient Withdrawal and Replacement ......................................................... 20 
2.7.1 Discontinuation from Treatment .............................................................. 20 
2.7.2 Discontinuation from Study ..................................................................... 20 
3 Study Conduct ................................................................................................... 22 
3.1 
Study Restrictions ....................................................................................... 22 
3.1.1 Granulocyte Colony-Stimulating Factor (GCSF) ..................................... 22 
3.1.2 Substrates of P-glycoprotein ................................................................... 22 
3.1.3 Other Anticancer Therapy ....................................................................... 23 
3.1.4 Vaccines ................................................................................................. 23 
3.1.5 Contraception ......................................................................................... 23 
3.1.5.1 Guidelines for Contraception .......................................................... 23 
3.1.5.2 Exemptions to Contraception .......................................................... 23 
3.1.6 Blood Donation ....................................................................................... 24 


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3.1.7 Optimal Antiemetic and Antidiarrheal Prophylaxis or Treatment  ........... 24 
3.2 
Study Schedule of Procedures .................................................................... 24 
3.3 
Procedures by Visit ..................................................................................... 24 
3.3.1 Screening Procedures/Enrollment (Visit 1, Day -28 to Day -1) ............... 24 
3.3.2 On Study ................................................................................................ 25 
3.3.3 End of Treatment (within 7 days of last dose) ......................................... 25 
3.3.4 Ongoing Assessments ............................................................................ 26 
3.3.5 Unscheduled Assessments .................................................................... 26 
4 Study Medication ............................................................................................... 28 
4.1 
Other Agent Used in Combination .............................................................. 28 
4.1.1 Administration ......................................................................................... 28 
4.1.2 Dose Modification ................................................................................... 28 
4.1.3 Toxicity Management.............................................................................. 28 
4.1.4 Packaging, Labeling and Storage ........................................................... 28 
4.1.5 Disposal and Destruction ........................................................................ 28 
4.2 
Niraparib ..................................................................................................... 28 
4.2.1 Identity .................................................................................................... 28 
4.2.2 Administration ......................................................................................... 29 
4.2.3 Potential Risks of Niraparib..................................................................... 29 
4.2.4 Dose Modification ................................................................................... 29 
4.2.5 Packaging, Labeling ............................................................................... 32 
4.2.6 Disposal and Destruction ........................................................................ 32 
4.2.7 Previous and Concomitant Medications .................................................. 32 
4.3 
Dose-Limiting Toxicity (DLT) ....................................................................... 32 
5 Statistical Methods ............................................................................................ 33 
5.1 
Safety Analyses .......................................................................................... 34 
5.2 
Determination of Sample Size n/a ............................................................... 35 
5.3 
Missing Data n/a ......................................................................................... 35 
5.4 
Interim Analysis n/a ..................................................................................... 35 
6 Ethical, Legal and Administrative Aspects ........................................................ 36 
6.1 
Good Clinical Practice ................................................................................. 36 
6.2 
Informed Consent ....................................................................................... 36 
6.3 
Protocol Approval and Amendment ............................................................. 36 
6.4 
Subject Confidentiality and Data Protection ................................................ 36 
6.5 
Data Quality Assurance .............................................................................. 37 
6.6 
Access to Source Documents ..................................................................... 37 
6.7 
Study Monitoring ......................................................................................... 38 
6.8 
Reporting Product Quality Complaints for Niraparib .................................... 39 


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6.9 
Reporting Adverse Events .......................................................................... 39 
6.9.1 
Recording of Adverse Events ............................................................... 39 
6.9.2 
Assessment of Adverse Events ............................................................ 39 
6.9.3 
Reporting Serious Adverse Events (SAEs) ........................................... 40 
6.9.4 
Follow-up of Adverse Events ................................................................ 40 
6.9.5 
Adverse Events of Special Interest (AESI) for Niraparib ...................... 41 
6.9.6 
Suspected Unexpected Serious Adverse Reactions (SUSARs) ........... 41 
6.9.7 
Pregnancy ............................................................................................ 41 
6.9.8 
Sponsor SAE and Pregnancy Reporting to GSK  ................................. 42 
6.10 Investigational Product ................................................................................ 43 
6.10.1 Dispensing ............................................................................................ 43 
6.10.2 Drug Accountability ............................................................................... 44 
6.11 Publications ................................................................................................ 44 
7 Schedule of Events ............................................................................................ 45 
8 References ......................................................................................................... 47 
Appendix 1 – Performance Status ......................................................................... 50 
Appendix 2 – Substrates of CYP1A2 ..................................................................... 51 
Appendix 3 – Criteria for Progressive Disease ..................................................... 53 
Appendix 4 – Therapy-related symptoms checklist (TRSC) ................................ 60 
Appendix 5 – WHO MDS Classification criteria .................................................... 61 
Appendix 6 – Health-Related Quality of Life (HRQOL), Linear Analogue Self-
Assessment (LASA) ................................................................................................ 63 
Appendix 7 – DECLARATION OF HELSINKI ......................................................... 64 
Appendix 8 – Safety Reporting information .......................................................... 69 
Appendix 9 – Health Related Quality of Life Assessment………………………....70 
Appendix 10 – Therapy Related Symptoms Checklist……………………………...71 


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LIST OF ABBREVIATIONS AND DEFINITIONS 
Table 1 
List of Abbreviations 
 
Abbreviation 
Definition 
ADP 
adenosine diphosphate 
AE 
adverse event 
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 
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 
HR 
homologous recombination 
HRD 
homologous recombination deficiency 
MRI 
magnetic resonance imaging 
MTD 
maximum tolerated dose 
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 
SAE 
serious adverse event 
TEAE 
treatment emergent adverse event 
TMZ 
temozolomide 
ULN 
upper limit normal 


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1 
INTRODUCTION 
 
1.1 
General Background 
The treatment of patients with advanced cancer remains unsatisfactory. New 
combinations are needed to improve the outcomes for patients with advanced 
disease. Thus, successful treatment of ovarian and breast cancer represents a 
great challenge. The optimal combination, sequencing of treatment, and schedule 
for targeted drugs and chemotherapy has not been optimally established. Little is 
also known regarding the unique molecular characteristics and patterns of each 
individual’s cancer tumor cells. New pathway-driven molecular subtypes are just now 
being elucidated1 and clinical trials with molecularly targeted therapy, for example, in 
the different types of ovarian and breast tumors are urgently needed using theranostic 
information2,3. 
Therapies are being developed to primarily reduce signaling via oncogenic 
intracellular pathways and thereby change transcriptional events that take place 
within the cancer cell nucleus. These novel therapies may potentially benefit not only 
ovarian and breast cancer patients but all tumor types and at all stages in the cancer 
process. Previously, factors used to make traditional chemotherapy decisions were 
based on the tissue of origin or histological subtype. But now, in the era of precision 
medicine, therapeutic strategies must be based on the degree of addiction of an 
individual tumor to the pathway being targeted. Identifying the oncogenic drivers of 
solid tumors and having drugs that target these drivers and/or pathways are the keys 
to the successful treatment of cancer in the future. 
 
1.2 
Ovarian Cancer 
As an example of solid tumors in women, ovarian cancer is the seventh most 
common cancer in women (and the 18th most common cancer overall) worldwide. 
Approximately 239,000 cases were recorded in 2012, accounting for nearly 4 percent 
of all new cases of cancer in women (2 percent overall). This cancer is usually 
fatal, and is the eighth most common cause of cancer death in women worldwide 
(14th overall)4. Cancers of the ovary, fallopian tube, and peritoneal origin exhibit 
similar behaviors and clinical and molecular characteristics. As such, these are often 
combined together and define epithelial ovarian cancer (EOC). About 85– 90% of 
ovarian cancers are epithelial carcinomas. 
Patients with ovarian cancer often have no symptoms at the early stages, so the 
disease is generally advanced when it is diagnosed. Approximately 75 percent of 
women have stage III (disease that has spread throughout the peritoneal cavity or 
that involves lymph nodes) or stage IV (disease spread to more distant sites) disease 
at diagnosis. The 5-year survival rate ranges from approximately 30–50%5,6. Risk 
increases with age, although the rate of increase slows after the menopause. Only 
10–15% of cases occur before menopause. 
Classically, EOC is treated with primary debulking surgery (PDS) followed by 
adjuvant platinum and taxane-based chemotherapy. However, for poor surgical 


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candidates and patients in whom an optimal cytoreduction (residual disease <10 
mm) is not feasible, neoadjuvant chemotherapy (NACT) prior to interval surgery and 
adjuvant chemotherapy is an alternative option. The search for novel therapeutic 
combinations and strategies that will drive precision medicine are paramount if we 
are to make a dent in increasing survival rates. 
 
1.3 
Breast Cancer 
In the United States, approximately 180,000 new cases of breast cancer occur 
annually, and there are more than 40,000 deaths7. More than 150,000 cases develop 
each year in Canada and the European community together, resulting in over 
60,000 deaths from breast cancer7. The vast majority of patients who die from breast 
cancer succumb to metastatic disease. 
Breast cancer is currently viewed as a complex family of diseases with individual 
molecular features and corresponding behaviors8. Early research in breast cancer 
identified the role of estrogen and estrogen receptors in tumor stimulation and growth. 
This discovery led to the development and approval in 1977, of the very first 
molecularly targeted cancer therapy, tamoxifen, for the treatment of metastatic breast 
cancer9,10. Significant advances have also been made in identifying genetic risk 
factors, e.g. BRCA-1 and BRCA-2, and other preventive strategies. Gene assays of 
breast tumor cells have been developed to estimate and predict the risk ratio of 
disease recurrence with and without adjuvant therapy11,12. 
Endocrine therapy and chemotherapy (using either sequential single agents or 
combination regimens) remain the principal treatments for women with metastatic 
breast cancer. The success of endocrine therapy is dependent on tight regulation of 
breast cell growth by steroids and growth factor receptors13. However, as cancer 
progresses, it usually becomes resistant to antiestrogens, and most patients 
eventually stop responding to endocrine therapy. In addition, a significant number of 
women have hormone receptor negative metastatic breast cancer that is not 
amenable to targeted therapies based on overexpression of ER, PR and/or HER2 
receptor families. A wide variety of classes of chemotherapeutic agents have activity 
as single agents. While the use of polychemotherapy (combination) regimens is 
usually associated with higher response rates when compared with single-agent 
treatment14, it is not clear that the enhanced response rates obtainable with currently 
available combination regimens correlate with clinically meaningful improvements in 
survival. Median survival remains approximately two years for women with 
metastatic breast cancer, and less than 3% of patients will experience long-term 
survival after treatment15. 
Thus, many women continue to die from breast cancer, primarily due to 
complications related to metastatic disease. Despite numerous new and old 
chemotherapeutic, biologic and hormonal therapies available to treat metastatic 
breast cancer, it remains the second leading cause of death in American women 
with 39,520 deaths estimated for 2011, second only to lung cancer16. Clearly a new 
approach in treating advanced breast cancer is needed and therefore, the 


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development of new treatment strategies is essential to improving outcomes for 
patients with advanced breast cancer. 
 
1.4 
Background of PARP and PARP Inhibition 
The PARP family consists of 17 members of which PARPs- 1, -2, -5A, and -5B, 
uniquely catalyze the transfer of multiple ADP-ribose units17,18. PARP1 and 2 are 
zinc-finger DNA binding enzymes that play a crucial role in DNA repair. Upon formation 
of DNA breaks, PARP binds at the end of broken DNA strands, a process that 
activates its enzymatic activity. Activated PARP catalyzes addition of long polymers 
of ADP-ribose onto PARP and several other proteins associated with chromatin, 
including histones and various DNA repair proteins. 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 (DNA replication) phase 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 recombination19. 
Homologous recombination is the preferred repair pathway because it is associated 
with a much lower error rate than other forms of repair. Cells unable to perform DNA 
repair via homologous recombination (e.g., due to inactivation of genes required for 
homologous recombination, such as breast cancer gene 1 [BRCA1] or BRCA2) are 
at risk for accumulating multiple lesions that will ultimately trigger apoptosis20. 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 mutations that promote 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. 
 
1.5 
Background on Homologous Recombination Deficiency (HRD) 
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 nonhomologous end-joining (NHEJ), alternative (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. Non-BRCA deficiencies in homologous recombination DNA repair 
genes could also enhance tumor cell sensitivity to PARP inhibitors. The rationale for 


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anticancer activity in a subset of non-gBRCAmut tumors is that they share distinctive 
DNA repair defects with gBRCAmut carriers, a phenomenon broadly described as 
“BRCAness.”21 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 defects22. A subset of 
these tumors had biologically plausible molecular alterations that may make them 
sensitive to PARP inhibition by niraparib. This concept of inducing death by use of 
PARP inhibitors to block one DNA repair pathway in tumors with pre-existing 
deficiencies in a complementary DNA repair pathways is called synthetic lethality23, 
the two insults together induce cell death when neither alone would have this effect. 
 
1.6 
Background of Niraparib 
Niraparib is an orally active PARP1/2 inhibitor with nanomolar potency24 being 
developed as a monotherapy agent for tumors with defects in the homologous 
recombination DNA repair pathway or that are driven by PARP-mediated transcription 
factors. Proof of principle was also obtained using preclinical in vivo xenograft 
BRCA mutant tumor models reviewed in Jones et al24. 
 
1.6.1 Phase 1 Clinical Studies 
Five Phase 1 clinical studies (PN001, PN005, PN008, PN011, and PN014) were 
conducted in 144 patients. Patients enrolled in these studies who were tolerating 
treatment without significant safety issues or evidence of disease progression could 
continue to receive study therapy provided the Investigator felt that such treatment 
was in the best interest of the patient. Such actions would not preclude the possibility 
of future studies with niraparib as single-agent therapy or in combination with other 
investigative agents. 
 
1.6.2 Phase 3 Study (PR-30-5011-C) 
The main study of PR-30-5011-C is a double-blind, 2:1 randomized, placebo-
controlled study in platinum-sensitive ovarian cancer patients who have either 
gBRCAmut or a tumor with high-grade serous histology. The patients must have 
received at least 2 platinum-based regimens, had a response to their last regimen, 
and have no measurable disease >2cm and normal CA-125 (or >90% decrease) 
following their last treatment. The study will assess whether maintenance with 
niraparib will extend progression-free survival (PFS) in this population. There are 2 
independent patient cohorts in this study, one cohort of patients with deleterious 
gBRCA mutations (gBRCAmut) and the other composed of patients with high-grade 
serous histology but without such gBRCA mutations (non-gBRCAmut) based on the 
hypothesis that patients with gBRCA mutations will be enriched for responsiveness 
to niraparib. Study treatment is dispensed to patients on Day 1 and every cycle (28 
days) thereafter until the patient discontinues study treatment. Study treatment is 
administered orally QD continuously. Three capsules of 100-mg strength are taken 
at each dose administration. Clinic visits occur in each cycle (every 4 weeks ± 3 
days). Response Evaluation Criteria in Solid Tumors tumor assessment via 


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computed tomography (CT) or magnetic resonance imaging (MRI) scan of 
abdomen/pelvis and clinically indicated areas is required at the end of every 2 cycles 
(8 weeks with a window of ± 7 days from date of visit) through Cycle 14, then at the 
end of every 3 cycles (12 weeks with a window of ± 7 days from date of visit) until 
progression. 
PR-30-5011-C also contains a 14-day, open-label, 2-treatment, crossover sub-study 
to evaluate the effect of a high fat meal on niraparib (single dose) exposure. For this 
food effect (FE) sub-study, entry criteria were broadened to include patients with 
ovarian cancer regardless of platinum sensitivity and burden of disease as long as 
no standard therapy exists or the patient refused standard therapy. In Group A, 
patients fasted (nothing to eat or drink except water) for at least 10 hours before 
receiving a single dose of 300 mg niraparib; patients continued to fast for at least 2 
hours following the dose. In Group B, patients fasted for at least 10 hours before 
consuming a high fat meal. Within 5 minutes of finishing the meal, a single dose of 
300 mg niraparib was administered orally and patients resumed fasting for at least 4 
hours. After a 7-day PK assessment and wash-out period, all patients received their 
second single dose of niraparib on Day 8 under the opposite (fasting vs high fat 
meal) circumstance. After the completion of the 14-day food effect sub-study, patients 
began daily dosing at 300 mg QD niraparib on Cycle 1/Day 1. 
 
1.6.3 Baseline 
Platelet 
Count 
and 
Weight 
as 
Predictors 
of 
Thrombocytopenia 
An analysis was conducted using the data collected in ENGOT-OV16/NOVA and the 
initial phase I study, PN001. This analysis determined that only baseline platelets had 
an impact on platelet nadir; lower baseline platelets (<180,000 µL ) were associated 
with an increased frequency of thrombocytopenia Grade ≥1 (76%) or Grade ≥ 3 (45%) 
compared to patients with higher baseline platelet counts. Further, an exploratory 
analysis of clinical data versus baseline body weight from ENGOT-OV16/NOVA was 
conducted.  For this analysis, the weight categories were based on quartiles with the 
lowest quartile (patients with a body weight less than 58 kg at baseline) compared to 
the highest quartile (patients with a body weight greater than or equal to 77 kg at 
baseline).  While TEAEs occurred in most patients regardless of body weight, Grade 
≥3 TEAEs, SAEs, and TEAEs leading to dose modification or treatment 
discontinuation occurred more commonly in the weight <58 kg cohort than in the ≥77 
kg cohort. In the cohort of patients with a body weight <58 kg, approximately 80% of 
patients had a dose reduction compared to 59% of patients with a weight greater than 
or equal to 77 kg. Treatment discontinuations were increased in the subjects with 
lower body weight (24%) compared to patients in the highest quartile (10%). 
The potential relationship between body weight and TEAEs was further explored in an 
analysis to evaluate the correlation of grade 3 or 4 thrombocytopenia and baseline 
body weight.  The lowest platelet count in the first 30 days was plotted versus baseline 
body weight to determine if low body weight identified a subgroup of patients with 
higher levels of thrombocytopenia during Cycle 1.  In the first 30 days of treatment, a 
baseline body weight >77 kg is associated with a lower incidence of grade 3 or 4 
thrombocytopenia (14%) relative to the group with body weight <58 kg (43%).  


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Finally, a classification tree approach was used to refine the best cut-off points for 
predicting the likelihood of a patient developing ≥Grade 3 thrombocytopenia within 30 
days after the first dose of niraparib.  The results of the model show that the subgroup 
of patients with a baseline body weight <77 kg or baseline platelet count <150,000 µL 
had a grade 3/4 thrombocytopenia rate in the first 30 days of 35.4% compared to 
11.5% in the group of patients with a body weight >77 kg and a platelet count >150,000 
µL. Further, the average daily dose was 258 mg through the first two cycles for patients 
with a body weight >77 kg and platelet count >150,000 µL, and was only 206 mg for 
patients with body weight < 77 kg or platelet count <150,000 µL. Thus, the actual 
delivered dose approximated a starting dose of 200 mg despite the intended delivery 
of a starting dose of 300 mg. These observations are to be confirmed in the present 
study with the inclusion of study treatment dosed at 200 mg (2 capsules of niraparib 
or placebo) in patients whose baseline weight is <77 kg or baseline platelet count is 
<150,000 µL. 
 
1.7 
PARP and mTOR inhibitors 
Studies are investigating ways to extend the use of PARP inhibitors in breast and 
other cancers despite previous inadequate and/or inconclusive data20,25. Various 
genes and signaling pathways have been implicated including the phosphoinositide 
3-kinase (PI3K) pathway that contributes to repair of DSBs in addition to its role in 
pro-proliferative and antiapoptotic functions in tumor cells26. Several studies have 
shown that the PI3K pathway that involves PI3K-related kinases including 
mammalian target of rapamycin (mTOR) are involved in DSB repair and the DNA- 
damage response (DDR)27,28. Furthermore, tumor cells became sensitized to 
cisplatin-mediated DNA damage–induced apoptosis when RAD001 (everolimus), an 
mTOR inhibitor, was added to cells27. Patients with sporadic triple negative breast 
cancer (TNBC) and/or basal-like breast tumors may have a certain degree of 
“BRCAness” that would open up the possibility of treating them with PARP inhibitors 
in combination with other drugs, potentially inhibitors of the PI3K-mTOR pathway29,30. 
Use of an mTOR inhibitor such as everolimus in combination with niraparib, could 
1) sensitize tumor cells to niraparib through blockade of PI3K- dependent DDR, and 
2) inhibit tumor growth mediated by PI3K-mTOR survival/proliferative signals. We 
have recently shown that PI3K-mTOR inhibition can sensitize BRCA1-competent 
TNBC to PARP inhibition in both in vitro and in vivo model systems, suggesting 
cooperation between the DDR and PI3K pathways29. 
The combination of a PARP inhibitor with everolimus has promise in the treatment of 
sporadic TNBC that displays “BRCAness” characteristics. In a similar manner, other 
solid tumors including ovarian, in which “BRCAness” is also found could benefit from 
the combination of niraparib and everolimus. Thus, the use of this combination in a 
phase I cancer clinical trial merits further investigation. 
 
 


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1.8 
Rationale for Current Study 
PARP is a very promising target for the treatment of many malignancies. As a nick- 
sensor, PARP binds to and initiates the repair of DNA SSBs. A failure to repair these 
events leads to persistent SSBs, which otherwise would get converted into 
potentially clastogenic or lethal DSBs at the “replication fork.” 
Correction of DSBs occurs through either homologous recombination (HR) or 
nonhomologous end joining (NHEJ). Thus, PARP inhibitors (PARPi) have potential 
chemosensitizing, radiosensitizing, and antineoplastic activities. 
The phosphoinositide 3-kinase (PI3K) enzyme contributes to repair of DSBs in 
addition to its role in pro-proliferative and antiapoptotic functions in tumor cells. 
Recently, the PI3K enzyme has been demonstrated to play a critical role in RAD51 
recruitment31. The PI3K signaling pathway has been reported to maintain HR steady 
state and stabilize and preserve DSB repair by interacting with the HR complex26. 
Suppression of PI3K function has been shown to impair HR32. mTOR, as a family 
member of PI3K-related protein kinases including ATM, ATR and DNA-PK, was also 
reported to be involved in DDR27,28. The kinase activity of mTOR has been 
particularly known to integrate nutrient/energy signaling with that of growth factor 
signaling in highly dividing tumor cells33-35. 
In our laboratory, we have shown through multiple preclinical experiments that the 
combination of a PI3K inhibitor or an mTOR inhibitor with a PARP inhibitor is 
synergistic in multiple cancer cell lines and ex vivo models. We propose to combine 
everolimus and niraparib in a phase I trial to determine the safety profile of this 
combination in advanced gynecologic malignancies and breast tumors. 
 
 


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2 
OVERALL DESIGN AND PLAN OF THE STUDY 
 
2.1 
Overview 
Open-label, cohort study to determine the feasibility and tolerability of the 
combination of daily niraparib and daily or thrice weekly everolimus for one 28-day 
cycle in patients with advanced gynecologic malignancies and breast cancer. 
 
Figure 1: Study Design. Dosing schema, 3–6 patients per cohort. 
 
The goal of this study is to determine a maximum tolerated dose (MTD) of the 
combination of niraparib and everolimus. To do this, we will estimate the MTD that is 
defined as the dose level at which less than one-third of patients will experience a 
dose-limiting toxicity (DLT). A traditional dose escalation design will be used, 
beginning with the lowest dose level and escalating to the maximum allowable dose 
level as specified in the protocol. A maximum of 4 dosing levels results in a maximum 
sample size of n=24 subjects. Adverse events will be defined using the Common 
Toxicity Criteria v.4.03. 
 
One of the following outcomes will determine the treatment of subsequent patients: 
• If none of the three patients experiences a DLT, the next group of patients will 
be entered in the next higher dose cohort. All patients within a cohort must have 
completed at least one cycle (28 days) prior to initiation of the next cohort of 
patients. 
• If one of the three patients experiences a DLT, three more patients will be 
accrued at the current dose level. Subsequently, if only one of the six patients 
treated at this level experiences a DLT, the dose will be escalated to the next 
higher dose in the next group of patients. If two or more of the six patients 
experiences a DLT, the MTD has been exceeded and is defined as the previous 
dose at which no more than 1/3 experienced a DLT. 
• If at least two of the three experience a DLT, the MTD has been exceeded and 
is defined as the previous dose at which no more than 1/3 experienced a DLT. 
If the lowest allowable dose level exceeds the MTD, the study will be terminated and 


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the combination will not be deemed safe for use in this population. Additionally, the 
highest dose level will not be exceeded, even if no DLTs are experienced at that 
dose. 
Once the MTD has been exceeded and this is not the lowest allowable dose, the 
investigators may drop down to the previous cohort and enroll an additional 6 patients 
to further confirm the safety and tolerability of the MTD.  
We will summarize the adverse events overall and by individual AE categories. 
Serious adverse events will be summarized in a similar manner. These summaries 
will be performed overall and for each dose cohort. We will summarize all events as 
well as the highest grade for a given subject. We will summarize the number of 
subjects that exhibit a DLT at each dose cohort and describe the DLT for each 
subject, if applicable. 
 
Cohort 1: (each cycle is 28 days long) 
Everolimus 5mg daily on Mondays, Wednesdays, and Fridays 
Niraparib 100mg daily 
 
Cohorts 2-4 are closed to future enrollment as of April 2020.  
 
Cohort 2: (each cycle is 28 days long) 
Everolimus 5 mg daily on Mondays, Wednesdays, and Fridays 
Niraparib 200 mg daily 
 
Cohort 3: (each cycle is 28 days long) 
Everolimus 2.5 mg daily 
Niraparib 200 mg daily 
 
Cohort 4: (each cycle is 28 days long) 
Everolimus 5 mg daily 
Niraparib 200 mg daily 
 
2.2 Primary Objective 
• To determine the maximum tolerated dose of the combination of niraparib and 
everolimus for the treatment of patients with advanced gynecologic 
malignancies or breast cancer 
 
2.3 Secondary Objectives 
• To assess the toxicity of the combination of niraparib and everolimus in each 
cohort 
• To determine the response rate (according to RECIST 1.1 response criteria) 
 
2.4 Exploratory Objectives 


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• To assess whether patients with certain molecular aberrations, using 
FoundationOne and/or cell-free DNA (cfDNA) or circulating tumor cells (CTCs) 
responded more favorably to the combination. 
• To describe symptom occurrence and severity and Health Related Quality of 
Life (HRQOL) as measured by the TRSC and HRQOL-LASA respectively. 
 
2.5 Inclusion Criteria 
a. Patients must have a gynecologic malignancy or breast cancer (triple 
negative or hormone receptor positive only) that is refractory/intolerant 
to all therapies known to confer clinical benefit in the advanced or metastatic 
setting or if the patient’s clinical team and the PI believe that the study treatment 
gives the patient the best chance for clinical benefit 
b. Patients w i t h  b r e a s t  c a n c e r  must have measurable disease per 
RECIST 1.1. criteria.  Patients with ovarian cancer are eligible with or without 
measurable disease  
c. Patients with ovarian cancer must have had appropriate surgical management 
for their disease and should be platinum resistant (recurrence within 6 months 
of last platinum-containing regimen) or be refractory to platinum-containing 
regimens 
d. Patients with endometrial, cervical, or any other advanced gynecologic 
malignancy must have already received or not be a candidate for all therapy 
proven to have a survival benefit 
e. Patients must have an Eastern Cooperative Oncology Group (ECOG) 
performance status of ≤2 
f. Patients must be ≥18 years of age 
g. Patients must have adequate organ function, defined as follows: 
• Absolute neutrophil count ≥1,500/µL 
• Platelets ≥125,000/µL 
• Hemoglobin ≥10 g/dL 
• Serum creatinine ≤1.5 x upper limit of normal (ULN) or calculated creatinine 
clearance ≥60 mL/min using the Cockcroft-Gault equation 
• Total bilirubin ≤ 1.5 x ULN 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 
h. Patient agrees to blood draws during screening and at the end of treatment for 
molecular and cytogenetic analysis 
i. Female patients of childbearing potential must have a negative serum 
pregnancy test (beta hCG) at Screening 
j. Female patients of childbearing potential must agree to use an acceptable 


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method of birth control (excluding hormonal birth control methods, see Section 
3.0.5) for 72 hours prior to initiation of therapy and to continue its use during the 
study and for at least 30 days after the final dose or as directed by the 
Investigator Brochure. 
k. Male patients must agree to use an acceptable form of birth control (see Section 
3.0.5) from study Day 1 through at least 90 days after the final dose or as 
directed by the Investigator Brochure. 
l. Patients must be able to understand the study procedures and agree to 
participate in the study by providing written informed consent 
 
2.6 Exclusion Criteria 
a. Patients with HER2+ breast cancer measured by standard IHC or FISH testing  
b. Patients must not be simultaneously enrolled in any other interventional clinical 
trial 
c. Patients must not have had major surgery ≤3 weeks of starting the study and 
patient must have recovered from any effects of any major surgery 
d. Patients must not have had investigational therapy administered ≤4 weeks, or 
within a time interval less than at least 5 half-lives of the investigational agent, 
whichever is longer, prior to the first scheduled day of dosing in this study 
e. Patients must not have had radiotherapy encompassing >20% of the bone 
marrow 
f. Patients must not have received prior treatment with a known PARP inhibitor 
or have participated in a study where any treatment arm included administration 
of a known PARP inhibitor 
g. Patients must not have a known hypersensitivity to the components of 
niraparib, everolimus, rapamycin analogues, or the excipients 
h. Patients must not be immunocompromised (patients with splenectomy are 
allowed) 
i. Patients must not have had any known, persistent >Grade 2 toxicity from prior 
cancer therapy 
j. Patients must not have had any known, persistent (>4 weeks), ≥Grade 3 
hematological toxicity or fatigue from prior cancer therapy 
k. Patients must not have received a transfusion (platelets or red blood cells) ≤4 
weeks of the first dose of study treatment 
l. Patients must not have current evidence of any condition, therapy, or 
laboratory abnormality (including active or uncontrolled myelosuppression [ie, 
anemia, leukopenia, neutropenia, thrombocytopenia]) that might confound the 
results of the study or interfere with the patient's participation for the full 
duration of the study treatment or that makes it not in the best interest of the 
patient to participate 


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m. Patients must not have had diagnosis, detection, or treatment of another type 
of cancer ≤2 years prior to randomization (except basal or squamous cell 
carcinoma of the skin that has been definitively treated) 
n. Patients must not have known, symptomatic brain or leptomeningeal 
metastases 
o. Patients must not be considered a poor medical risk due to a serious, 
uncontrolled medical disorder, nonmalignant systemic disease, or active, 
uncontrolled infection. Examples include, but are not limited to, uncontrolled 
ventricular arrhythmia, recent 
(within 90 days) myocardial infarction, 
uncontrolled major seizure disorder,  
unstable 
spinal cord 
compression, 
superior vena cava syndrome, interstitial lung disease, HIV or Hepatitis B, or 
any psychiatric disorder that prohibits obtaining informed consent 
p. Patients must not have any known history of myelodysplastic syndrome (MDS) 
or acute myeloid leukemia (AML) 
q. Patient is a woman with a positive serum pregnancy test ≤3 days prior to 
study drug administration, is breast-feeding, or is planning to conceive children 
within the projected duration of the study treatment 
r. Patients with uncontrolled or poorly controlled hypertension. Patients with grade 
3 hypertension or above at baseline are not allowed unless controlled (grade 1 
or better) for at least three months.  
s. Patients taking ACE inhibitors (patients that have no known medical reason to 
require therapy with ACE inhibitors may be switched to another appropriate 
antihypertensive treatment prior to initiation of study treatment) 
t. Patients taking strong or moderate CYP3A4/PgP inhibitors or strong 
CYP3A4/PgP inducers (appendix 2) (if medically appropriate, patients may be 
switched to another appropriate therapy at least 14 days prior to initiation of 
study treatment) 
 
2.7 Patient Withdrawal and Replacement 
 
2.7.1 Discontinuation from Treatment 
Patients may be discontinued from study treatment at any time. Specific reasons for 
discontinuing treatment include the following: 
a. Serious or life-threatening adverse event 
b. Risk to patients as judged by the Investigator and/or Sponsor 
c. Severe noncompliance with protocol as judged by the Investigator and/or 
Sponsor 
d. Request of the patient 
e. Patient becomes pregnant 
f. Progressive disease 


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g. Investigator becomes aware of conditions or events that suggest a possible 
hazard to patients if the clinical study continues 
h. Patient is diagnosed with MDS or AML (as confirmed by a hematologist) 
i. Patient is diagnosed with PRES 
 
2.7.2 Discontinuation from Study 
The investigator/treating physician will make every reasonable effort to keep each 
patient on study. However, if the investigator/treating physician removes a patient 
from the study or if the patient declines further participation, a final assessment of 
the patient’s disease status should be performed prior to any therapeutic 
intervention. These results, together with a description of the reason for study 
discontinuation, must be recorded in the CRF. 
Patients who discontinue from treatment 
will continue to receive follow-up 
assessments as part of the study unless they are discontinued from study by one of 
the following events: 
• Withdrawal of consent or HIPAA Authorization 
• Loss to follow-up 
• Death from any cause 
• Termination of the study 
For patients who are thought to be lost to follow-up, at least 3 documented attempts, 
including 1 via certified mail, should be made to contact the patient before the 
patient is deemed lost to follow-up. 
 
 


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3 STUDY CONDUCT 
 
3.1 Study Restrictions 
 
3.1.1 Granulocyte Colony-Stimulating Factor (GCSF) 
Prophylactic 
cytokine 
(Granulocyte 
Colony-Stimulating 
Factor 
[GCSF]) 
administration should not be given in the first cycle of the study, but may be 
administered in subsequent cycles according to local guidelines and Section 4.1.4. 
 
3.1.2 Substrates of P-glycoprotein or Cytochrome P450 
Niraparib has shown limited interactions with other drugs (see Appendix 2). The 
niraparib safety profile includes risk for thrombocytopenia; therefore, patients should 
be advised to use caution with anticoagulation and antiplatelet drugs. 
Co-administration of everolimus with strong inhibitors or inducers of CYP3A4 or PgP 
should be avoided; they may cause changes in everolimus concentrations. For a 
current complete listing of cytochrome P450 metabolized medications please access 
the following website: www.Medicine.iupui.edu/clinpharm/ddis/table.asp. If this 
website is not operative, please search using Flockart DA. Drug Interactions: 
Cytochrome P450 Drug Interaction Table. 
Examples of agents that may increase everolimus blood concentrations: 
Everolimus blood concentrations may be increased by substances that inhibit CYP3A4 
activity and thus decrease everolimus metabolism. Everolimus blood concentrations 
may be increased by inhibitors of PgP that may decrease the efflux of everolimus from 
intestinal cells. Concurrent treatment with strong inhibitors of CYP3A4 or PgP 
(including but not limited to ketoconazole, itraconazole, ritonavir, clarithromycin and 
telythromycin) should be avoided. Use caution when administered in combination with 
moderate CYP3A4 inhibitors or PgP inhibitors. If everolimus must be co-administered 
with a moderate CYP3A4 or PgP inhibitor, the patient should be carefully monitored 
for undesirable effects and the dose reduced if necessary. Concomitant treatment with 
moderate inhibitors of CYP3A4 including but not limited to erythromycin, verapamil, 
fluconazole, diltiazem, amprenavir, fosamprenavir, or aprepitant) and PgP inhibitors 
requires caution. Other moderate inhibitors of CYP3A4 and PgP that may increase 
everolimus blood concentrations include certain antifungal agents (e.g. fluconazole) 
and calcium channel blockers (e.g. diltiazem). Grapefruit, grapefruit juice and other 
foods that are known to affect cytochrome P450 and PgP activity should be avoided 
during treatment. 
Agents that may decrease everolimus blood concentrations: Substances that are 
inducers of CYP3A4 or PgP may decrease everolimus blood concentrations by 
increasing metabolism or the efflux of everolimus from intestinal cells. Concurrent 
treatment with strong inducers of CYP3A4 or PgP should be avoided. If everolimus 
must be co-administered with a strong CYP3A4 or PgP inducer (e.g. rifampicin and 
rifabutin), it may be necessary to adjust the dose. Other strong inducers of CYP3A4 
that may increase the metabolism of everolimus and decrease everolimus blood levels 
include St. John’s wort (Hypericum perforatum), corticosteroids (e.g. dexamethasone, 


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prednisone, prednisolone), anticonvulsants (e.g. carbamazepine, phenobarbital, 
phenytoin,) and anti-HIV agents (e.g. efavirenz, nevirapine). 
 
3.1.3 Other Anticancer Therapy 
No other anticancer therapy is permitted during the course of the study treatment for 
any patient (the patient can receive a stable dose of corticosteroids during the study 
as long as these were started at least 4 weeks prior to enrollment, per exclusion 
criteria above). If the patient discontinues study treatment, this restriction no longer 
applies, however the patient will remain enrolled in the study for the purpose of 
collecting subsequent outcomes. Palliative radiotherapy (excluding the pelvic region 
and/or palliative radiotherapy encompassing >20% of the bone marrow within 1 
week of the first dose of study treatment) is allowed for pre-existing small areas of 
painful metastases that cannot be managed with local or systemic analgesics as 
long as no evidence of disease progression is present. 
 
3.1.4 Vaccines 
An increased risk of infection by the administration of live virus and bacterial vaccines 
has been observed with conventional chemotherapy drugs. Effects with niraparib 
are unknown and therefore they should not be administered to patients in the study. 
All patients will be instructed to not receive a vaccination with a live virus vaccine 
until at least 30 days after the completion of the treatment, starting at the time of 
consent. 
 
3.1.5 Contraception 
 
3.1.5.1 Guidelines for Contraception 
All male and female subjects who are not surgically sterile or post-menopausal are 
required to use two forms of birth control with the use of a condom (male or female 
condom; with or without spermicide) required as one of the forms of birth control. 
Acceptable methods of contraception in addition to the use of a condom (male and 
female; with or without spermicide) include: 
Female study subjects: non-hormonal intrauterine device (IUD) or diaphragm with 
spermicide 
Female partner of study subjects: non-hormonal IUD, diaphragm with spermicide, or 
hormonal birth control (e.g., pills, IUD [hormonal or non-hormonal], NuvaRing) 
 
3.1.5.2 Exemptions to Contraception 
Patients must be postmenopausal, free from menses for >1 year, surgically 
sterilized, willing to use adequate contraception to prevent pregnancy, or agree to 
abstain from activities that could result in pregnancy from enrollment through3 0  
days after the last dose of study treatment 
 
 


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3.1.6 Blood Donation 
Patients must not donate blood during the study or for 90 days after the last dose of 
study treatment. 
 
3.1.7 Optimal Antiemetic and Antidiarrheal Prophylaxis or Treatment 
Patients should avoid use of corticosteroids and NK-1 antagonists as antiemetic 
prophylaxis or treatment due to drug interactions. Antiemetic prophylaxis is not 
recommended at the initiation of study treatment. If antiemetic therapy is required, it is 
recommended that ondansetron 8mg po q8 prn be the treatment of choice. Additional 
interventions should be discussed with the principle investigator.  
Antidiarrheal therapy is also not recommended at the initiation of study treatment. If 
therapy is required, it is recommended that loperamide 4mg followed by 2mg every 4 
hours or after each unformed stool be the standard treatment.   
 
3.2 Study Schedule of Procedures 
An overview of the study is provided in the study schedule and is shown in the 
Schedule of Events in Section 7. 
 
3.3 Procedures by Visit 
 
3.3.1 Screening Procedures/Enrollment (Visit 1, Day -28 to Day -1) 
All subjects must have signed and dated the informed consent and HIPAA 
Authorization prior to any study specific screening procedures being performed. Pre- 
enrollment screening test and evaluations will be used to determine the eligibility of 
the patient for study inclusion. All screening tests and procedures must be 
completed within 28 days prior to study registration and include the following: 
1) Demography and Medical History including documentation of prior regimen 
2) Vital signs including: temperature, BP, pulse, respiration rate, oxygen 
saturation 
3) Concomitant medications 
4) Performance Status–-ECOG 
5) CBC with differential and platelet count 
6) Biochemistries including: ALT/SGPT, AST/SGOT, alkaline phosphatase, total 
bilirubin, creatinine clearance (calculated using the Cockcroft formula) or 
creatinine and albumin 
7) Lipid panel 
8) Serum pregnancy test, required only for women of childbearing potential 
9) Tumor Assessment according to RECIST 1.1 (only if measurable lesions; 
patients will not be excluded if there are no measurable lesions if they have 
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10) Whole blood samples will be collected prior to the start of the study drug 
for cytogenetic analysis if required. Samples are to be collected in K2 EDTA 
tubes and labeled with the protocol number, patient ID, collection date, and 
visit type (screening, end of treatment, or other). All samples should be 
stored at -20C until ready for shipment if required. 
Once all screening procedures have been completed and laboratory values have 
been reported, the investigator/treating physician or their designee will register the 
patient in the study. 
 
3.3.2 On Study 
The active component of the study will be the first three cycles. The MTD will be 
assessed in the first cycle while cycles two and three will determine ongoing 
tolerability. After the completion of two cycles, patients will be assessed for disease 
response. Patients that have stable disease or disease response will be allowed to 
continue their treatment as long as there are no unacceptable toxicities and as long 
as their disease is stable or improving. 
For the purposes of this study the following evaluations will be performed during 
active therapy: 
1) Physical exam (including vital signs) 
2) ECOG performance status 
3) Concomitant medications 
4) Labs including CBC with differential and Comprehensive Metabolic Panel. 
CBC should be performed and monitored weekly from D14 until the end 
of the first cycle (D28) and then monthly thereafter 
5) Blood pressure monitoring should continue weekly for 2 cycles (8 weeks) 
through Cycle 3 Day 1, and if under adequate control per institutional protocols, 
monitoring may subsequently resume as described in Table 5 
6) Adverse Event Monitoring 
7) Completion of questionnaires – TRSC and HRQOL-LASA 
8) In the event that a patient is diagnosed with MDS/AML while on study, a bone 
marrow aspirate and biopsy will be completed, and a whole blood sample will 
be collected for molecular and cytogenetic analysis. 
9) After the completion of 2 cycles (56 days +/- 7 days) patients will be assessed 
for disease response utilizing the same analysis that was used at baseline and 
then again at 16 weeks (112 days +/- 7 days) if the patient has stable disease 
or better. If the patient continues on trial, scans may be performed every 8-
12 weeks thereafter at the discretion of the investigators. 
 
3.3.3 End of Treatment (within 7 days of last dose) 
1) Lipid Panel 
2) Whole blood sample for cytogenetic analysis 


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3) Adverse Event Monitoring 
4) Completion of questionnaires – TRSC and HRQOL-LASA 
 
3.3.4 Ongoing Assessments 
1) Disease status assessment to be performed every 8-12 weeks (i.e. every 56-
94 days +/- 7 days) at the discretion of the investigators 
2) Adverse events will be monitored for 30 days following the last dose 
3) Survival status will be monitored every 8 weeks for at least 2 years following 
the last dose 
4) In the event that a patient develops MDS/AML, the patient will be followed for 
at least 5 years following the last dose. 
 
3.3.5 Unscheduled Assessments 
1) 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's Pharmacovigilance 
Department within 24 hours of becoming aware of the SAE 
2) CBC: 
• 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 
weeks after the AE has been resolved to the specified levels, after which 
monitoring every 4 weeks may resume 
3) Chest CT or MRI: 
• If the chest CT or MRI is clear at Screening, repeat chest imaging is not 
required in the absence of lesions to be followed or in the absence of 
clinical indication requiring follow-up; otherwise, repeat chest imaging 
should be completed at the same time as RECIST imaging 
4) Bone marrow aspirate and biopsy: 
• For any suspected MDS/AML case reported while a patient is receiving 
treatment or 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 as long as the 
study site receives a copy of the hematologist’s report, which must 
include a classification according to World Health Organization criteria36. 
The site must keep a copy of the report with the patient’s study file. 
5) Exploratory: 
• To assess whether certain molecular aberrations responded more 


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favorably to the combination, tissue from a new or existing biopsy may be 
sent to Foundation Medicine for analysis. Additionally, sequencing DNA 
from the patients’ blood samples using cell-free DNA (cfDNA) or 
circulating tumor cells (CTCs) technology may be used as part of the 
analysis. In both cases, this will be carried out in a retrospective manner 
and patients will not be selected based on their molecular aberrations for 
this study. 
6) FoundationOne Assay 
• Foundation Medicine has developed its first clinical product, an NGS 
genomic assay that is used to identify alterations in all genes known to 
be somatically altered in human solid tumors based on recent scientific 
and clinical literature. The assay generates an informative genomic profile 
through interrogation of the entire coding sequence of 315 cancer-related 
genes plus select introns from 28 genes often rearranged or altered in 
solid tumors. The information obtained from this assay complements 
traditional cancer treatment decision tools and can often expand 
treatment options by matching each patient with targeted therapies and 
clinical trials that are relevant to the molecular changes in their tumor 
based on the most recent scientific and medical research. DNA from the 
patient is sequenced at great depth to hone in on the relevant, actionable 
somatic alterations, including single base pair changes, insertions, 
deletions, copy number alterations, and selected fusions. 
7) Cell Free DNA (cfDNA) and Circulating Tumor Cells (CTCs) 
• Plasma of cancer patients contains cell-free tumor nucleic acid that 
carries information on tumor mutations and tumor burden. A range of 
markers has been identified for specific tumor types. Nucleic acids are 
found in small amounts in healthy and diseased human plasma/serum. 
Higher levels of circulating nucleic acids are present in the plasma of 
cancer patients derived from tumor cells. 
 
 


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4 STUDY MEDICATION 
 
4.1 Other Agent Used in Combination: Everolimus 
Everolimus will not be supplied as part of this study. 
Everolimus is an antineoplastic agent. The chemical name of everolimus is 
(1R,9S,12S,15R,16E,18R,19R,21R,23S,24E,26E,28E,30S,35R)-1,18-dihydroxy-12- 
{(1R)-2-[(1S,3R,4R)-4-(2-hydroxyethoxy)-3-methoxycyclohexyl]-1-methylethyl}- 
19,30-dimethoxy-15,17,21,23,29,35-hexamethyl-11,36-dioxa-4-aza- 
tricyclo[30.3.1.9]hexatriaconta-16,24,26,28-tetraene-2,3,10,14,20-pentaone 
(everolimus package insert). 
 
4.1.1 Administration 
Everolimus 2.5 mg or 5 mg tablets will be used. Everolimus will be self-administered 
orally on a daily basis and doses will either be 5 mg (1 tablet) thrice weekly, 2.5 mg 
daily, or 5 mg daily depending on the cohort the patient is enrolled to. Patients may 
take the everolimus at the same time as the niraparib. Each cycle will be 28 days; 
everolimus will be taken continuously with no rest between cycles. 
 
4.1.2 Dose Modification 
No dose reductions of everolimus are allowed in cohort 1. 
 
4.1.3 Toxicity Management 
Adverse effects related to the use of everolimus should be managed based upon the 
information in the FDA approved package insert, published literature, and clinical 
discretion. It is suggested that all patients receive a steroid mouth rinse for the 
management of stomatitis. 
 
4.1.4 Packaging, Labeling and Storage 
Everolimus will be packaged and labeled according to pharmacy and local regulations. 
 
4.1.5 Disposal and Destruction 
Everolimus will be destroyed at the investigational site, if permitted, according to local 
regulations. 
 
4.2 Niraparib 
 
4.2.1 Identity 
Niraparib ([3S]-3-[4-{7-(aminocarbonyl)-2H-indazol-2-yl} phenyl] piperidine [tosylate 
monohydrate salt]) is an orally available, potent, highly selective PARP-1 and -2 
inhibitor. The excipients for niraparib are lactose monohydrate and magnesium 
stearate. 
 
4.2.2 Administration 


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Niraparib 100 mg will be administered orally QD continuously. Niraparib will be 
administered as a flat-fixed dose and not by body weight or body surface area. Each 
dose should be swallowed whole without chewing. The consumption of water is 
permissible. Patients should take doses at approximately the same times each 
day, and record this information in the patient diary. Patients will be provided with a 
diary in which to record their intake of study drug. However, the actual number of 
tablets taken by the patient must be calculated from the number of tablets dispensed 
and returned. 
Patients 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 each study drug is administered and that the drug accountability is performed. 
Patients may take the niraparib and the everolimus at the same time.   
 
4.2.3 Potential Risks of Niraparib 
The following adverse reactions (all CTCAE grades) have been reported in ≥20% of 
patients who received niraparib: anemia, thrombocytopenia, nausea, constipation, 
vomiting, fatigue, platelet count decreased, decreased appetite, headache, and 
insomnia. The median exposure to niraparib in these patients was 250 days. 
The following adverse reactions and laboratory abnormalities have been identified in 
≥10 to <20% of the 367 patients receiving niraparib: neutropenia, palpitations, 
asthenia, neutrophil count decreased, dizziness, dysgeusia, dyspnea, cough and 
hypertension. The following adverse reactions and laboratory abnormalities have 
been identified in ≥1 to <10% of the 367 patients receiving niraparib: tachycardia, dry 
mouth, mucosal inflammation, white blood cell count decreased, aspartate 
aminotransferase increased, alanine aminotransferase increased and photosensitivity 
reaction.  The following adverse reactionhas been identified in less than 0.1% of 
patients on clinical trials receiving niraparib: posterior reversible encephalopathy 
syndrome (PRES). 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. Guidance on monitoring patients for 
new events of MDS/AML and the follow-up of patients with suspected MDS/AML 
is provided in in Section 4.1.4 and Section 7. 
 
4.2.4 
Dose Modification  
Dose interruption may be implemented at any time for any grade toxicity considered 
intolerable by the patient. 
Treatment must be interrupted for any CTCAE (v.4) Grade 3 or 4 AE that the 
Investigator considers to be related to administration of niraparib. If toxicity is 
appropriately resolved to baseline or Grade 1 or less within 28 days of interruption, the 
patient may restart treatment with niraparib according to the tables below. 
If the event recurs at a similar or worse grade, treatment should be discontinued.  
If the toxicity requiring dose interruption has not resolved completely or to CTCAE 


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Grade 1 during the maximum 4-week (28-day) dose interruption period, the patient 
must permanently discontinue treatment with niraparib. 
 
Table 2. Cohort 1: Dose Reduction for Nonhematologic Toxicities 
Event 
Dose(1) 
Initial dose 
100 mg QD 
CTCAE Grade 3 or 4 treatment-related SAE/AE ≥ 28 days 
Discontinue 
study 
treatment 
Abbreviations: AE = adverse event, CTCAE = Common Terminology Criteria for Adverse Events, QD 
= once daily, SAE = serious adverse event 
(1) Dose not to be decreased below 100 mg QD 
 
The dose interruption/modification criteria for hematologic parameters will be based on 
blood counts and are outlined in Table 4. 
If the hematologic toxicity has not recovered to the specified levels within 4 weeks (28 
days) of the dose interruption period, the patient must permanently discontinue 
treatment with niraparib. 
If patients present with any of the following symptoms of Posterior Reversible 
Encephalopathy Syndrome (PRES), seizures, headache, altered mental status, visual 
disturbance, or cortical blindness (with or without associated hypertension), treatment 
should be held until neurologic examination and PRES is ruled out. A diagnosis of 
PRES requires confirmation by brain imaging, preferably MRI. In patients with 
confirmed PRES, treatment must be permanently discontinued. 
  
 


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Table 4: Dose Modification of Niraparib for Hematologic Toxicities 
Finding 
Modification 
Platelet count 75,000-
99,999/µL(1) 
Study treatment must be interrupted until platelet counts 
are ≥100,000/µL, with weekly blood counts for CBC 
monitored until recovery. Study treatment may then be 
resumed at same dose based on clinical judgment. 
2nd occurrence of platelet 
count 75,000-99,999/µL(1) 
Study treatment must be interrupted until platelet counts 
are ≥100,000/µL, with weekly blood counts for CBC 
monitored until recovery. Study treatment may then be 
resumed at the previous dose. 
Platelet count <75,000/µL(1) 
Study treatment must be interrupted until platelet counts 
are ≥100,000/µL, with weekly blood counts for CBC 
monitored until recovery. Study treatment may then be 
resumed the previous dose. 
Neutrophil <1,000/µL(2) 
Study treatment must be interrupted until neutrophil 
counts ≥ 1,500/µL, with weekly blood counts for CBC 
monitored until recovery. Study treatment may then be 
resumed at previous dose. 
Hemoglobin ≤8 g/dL 
Study treatment must be interrupted until hemoglobin is ≥ 
9 g/dL, with weekly blood counts for CBC monitored until 
recovery. Study treatment may then be resumed at  
previous dose. 
Abbreviations: CBC = complete blood count 
(1)If the platelet count has not reverted within 28 days of interruption to ≥100,000/µL, then the patient 
should be discontinued. 
(2)For patients with platelet count ≤ 10,000/μL, prophylactic platelet transfusion per guidelines may be 
considered37,38. For patients taking anticoagulation or antiplatelet drugs, consider the risk/benefit of 
interrupting these drugs and/or prophylactic transfusion at an alternate threshold, such as ≤ 
20,000/μL.  
In the case of thrombocytopenia, following the first occurrence, resumption of therapy 
may occur at the same dose when the hematologic toxicity has resolved. If the 
platelet count has not reverted within 28 days of interruption to ≥100,000/µL, then the 
patient should be discontinued. 
If dose interruption is required at any point on study because of hematologic 
toxicity, weekly blood draws for complete blood count (CBC) will be monitored 
until the AE resolves, and to ensure safety of the new dose, weekly blood draws for 
CBC will be also required for an additional 4 weeks after the AE has been resolved 
to the specified levels, after which monitoring every 4 weeks may resume. 
Any patient requiring transfusion of platelets or red blood cells (1 or more units) 
must be removed from the study. 
The patient must be referred to a hematologist for further evaluation (1) if 
transfusions are required on more than 1 occasion or (2) if the treatment-related 
hematologic toxicities have not recovered to CTCAE Grade 1 or less after 4 weeks. 
If a diagnosis of MDS/AML is confirmed by a hematologist, the patient must 
permanently discontinue study treatment. For major surgery while on treatment, up to 


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28 days of study treatment interruption is allowed. 
All dose interruptions and reductions (including any missed doses), and the reasons 
for the reductions/interruptions, are to be recorded. 
 
4.2.5 Packaging, Labeling 
Niraparib is supplied by GSK as 100 mg capsules packaged in high-density 
polyethylene (HDPE) bottles with child-resistant plastic closures. The study 
treatment will be open-label and will not be patient-specific. 
All study treatment supplies must be stored in accordance with the manufacturer’s 
instructions and package labeling. Until dispensed to the patients, the study 
treatment will be stored in a securely locked area, accessible to authorized 
personnel only. 
 
4.2.6 Disposal and Destruction 
Niraparib will be destroyed at the investigational site, if permitted, according to local 
regulations. 
 
4.2.7 Previous and Concomitant Medications 
Niraparib has shown limited interactions with other drugs. Please refer to Appendix 
2. 
 
4.3 Dose-Limiting Toxicity (DLT) 
DLT criteria for Adverse Event occurring in Cycle 1 while determining MTD: 
1) Grade 3 or higher nonhematologic toxicity, despite adequate treatment, except 
for Grade 3 rash lasting ≤3 days (all patients should receive topical steroid 
treatment, oral antihistamines, and oral steroids, if necessary). 
2) Grade 3 or greater nausea, vomiting, or diarrhea that persists > 48 hours despite 
maximal supportive care 
3) Grade 4 neutropenia lasting >7 days in the absence of growth factor support. 
4) Grade 3 or greater neutropenia of any duration accompanied by fever ≥38.5°C 
and/or systemic infection. 
5) Any other Grade ≥4 hematologic toxicity. 
6) Inability to administer at least 75% of planned doses of niraparib due to study 
drug-related toxicity. 
7) Any clinically significant occurrence that the investigator and sponsor agree 
would place patients at an undue safety risk. 
5 STATISTICAL METHODS 
The statistical analysis will be mainly descriptive. Continuous variables will be 
summarized using descriptive statistics: N, mean, standard deviation, median, 
minimum and maximum. Categorical variables will be presented using frequencies 


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and percentages. Time-to-event will be described by N, median, range, number 
censored, and Kaplan-Meier plots. 
All data collected on the CRF will be listed on a per-patient basis. There will be no 
imputations for missing data other than dates. A statistical analysis plan will be 
finalized prior to analysis. Any deviations from the statistical methods given in the 
protocol will be described and fully justified in the statistical analysis plan and/or in 
the final report as appropriate. 
Primary objective: 
We will estimate the MTD, which is defined as the dose level at which less than one- 
third of patients will experience a DLT. A traditional dose escalation design will be 
used, beginning with the lowest dose level and escalating to the maximum allowable 
dose level as specified in the protocol. Three patients will be treated at a given dose 
level; a maximum of 4 dosing levels results in a maximum sample size of N=24 
patients. 
One of the following outcomes will determine the treatment of subsequent patients: 
• If none of the three patients experiences a DLT, the next group of patients will 
be entered in the next higher dose cohort. All patients within a cohort must have 
completed at least once cycle (28 days) prior to initiation of the next cohort of 
patients. 
• If one of the three patients experiences a DLT, three more patients will be 
accrued at the current dose level. Subsequently, if only one of the six patients 
treated at this level experiences a DLT, the dose will be escalated to the next 
higher dose in the next group of patients. If two or more of the six patients 
experiences a DLT, the MTD has been exceeded and is defined as the previous 
dose at which no more than 1/3 experienced a DLT. 
• If at least two of the three experience a DLT, the MTD has been exceeded and 
is defined as the previous dose at which no more than 1/3 experienced a DLT. 
If the lowest allowable dose level exceeds the MTD, the study will be terminated and 
the combination will not be deemed safe for use in this population. Additionally, the 
highest dose level will not be exceeded, even if no DLTs are experienced at that 
dose. 
Secondary objective 1: 
Adverse events will be defined using the CTCAE v. 4.03. We will summarize the 
AEs overall and by individual AE categories. Serious adverse events will be 
summarized in a similar manner. These summaries will be performed overall and for 
each cohort. All events will be summarized as well as the highest grade for each 
dose cohort. The number of subjects that exhibit a DLT at each dose cohort will be 
summarized, and a description of the DLT for each subject (if applicable) will be 
provided. 
Secondary objective 2: Individual responses per RECIST criteria 1.1 will be reported 
if possible. An overall response rate will be calculated for the study population and 
reported as a frequency. 


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Tumor Assessment 
Radiographic response will be evaluated according to RECIST 1.1 criteria [57] (see 
Appendix 3) in all patients with measurable disease. Tumor assessments for 
evaluation of response will be conducted every 8 weeks x 2, and then every 8-12 
weeks thereafter until study discontinuation or disease progression, whichever is 
later. All sites of disease must be evaluated using the baseline assessment 
methods. Confirmatory assessment of complete response (CR) or partial response 
(PR) must be performed no less than 4 weeks after the initial documentation of 
response. 
Tumor marker assessments for those patients without measurable disease (GYN 
only) that had elevated levels on the last prior regimen will be taken at baseline and 
approximately every 8 ± 2 weeks along with tumor assessments during the study 
treatment period. All tumor marker assessments must be assayed by the same 
laboratory for each patient. All target lesions will be measured by consistent imaging 
techniques throughout the study. The same technique should be used for each 
evaluation in an individual patient. Results should be recorded in the CRF. Copies of 
the scans must be available for review. All patients who receive at least two 
treatment cycles and undergo at least one on-study disease assessment or 
experience early progression will be considered evaluable for response. 
Response Assessment for Gynecologic Patients Without Measurable Disease 
Many patients with advanced gynecological malignancies will not have target lesions 
per RECIST 1.1 due to the nature of the disease. To address this, the Gynecological 
Cancer Intergroup (GCIG) has reached consensus regarding the criteria for defining 
progression in clinical trials of recurrent disease, which has been validated and thus 
accepted in clinical trials39. For this study, patients with an ovarian malignancy 
without target lesions may still be included according to the GCIG consensus 
guidelines (please see Appendix 3). 
 
5.1 Safety Analyses 
Trained study coordinators and/or data managers will enter the information 
described in this section.  All adverse events (AE’s) will be presented in incidence 
tables coded by MedDRA type and body system. Additionally, separate AE 
incidence tables, coded by MedDRA type, will be presented by: 1) toxicity grade 
(severity) graded by the Common Terminology Criteria for Adverse Events v4.0 
(CTCAE); and 2) relationship to treatment as determined by the investigator/treating 
physician. 
All serious adverse events, discontinuations due to adverse event, or deaths 
occurring during the course of the trial or within 30 days following termination from 
the trial will be summarized on a per-patient basis. 
Survival information as well as information about patients who have developed 
MDS/AML will be collected every 8 weeks for at least 2 years from treatment initiation. 
 
5.2 Determination of Sample Size n/a 


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No power analysis to determine sample size will be done for this study since the 
primary objective is to determine the maximum tolerated dose of niraparib and 
everolimus. The sample size will be determined by the dose escalation design of the 
study. 
 
5.3 Missing Data n/a 
No imputation for missing data will be used. 
 
5.4 Interim Analysis n/a 
No efficacy analysis is planned. Safety data will be reviewed on an ongoing basis. 
 
 
 


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6 ETHICAL, LEGAL AND ADMINISTRATIVE ASPECTS 
 
6.1 Good Clinical Practice 
This study will be conducted in compliance with the protocol, the principles of Code 
of Federal Regulations (CFR), ICH GCP and the Declaration of Helsinki as amended 
in Edinburgh (2000) (Appendix 2). 
 
6.2 Informed Consent 
The principles of informed consent and GCP guidelines in FDA-Regulated Clinical 
Trials are described in the 21 CFR 50, Protection of Human Subjects. 
These regulations must be followed in conducting and monitoring clinical 
investigations. Consent for tumor biopsy and participation in the study will be obtained 
and documented. 
The investigator/physician will thoroughly explain to the patient the purpose and 
methods of the study, as well as any expected effects and adverse reactions, before 
any study-specific screening procedures are conducted. The patient will be provided 
with a copy of the consent and will be given sufficient time and opportunity to inquire 
about the details of the trial and to decide whether or not to participate. The patient 
and the person with whom the informed consent is discussed will sign and date the 
consent form. 
The investigator/treating physician will explain that the patient is completely free to 
refuse to enter the study or to withdraw from it at any time and for any reason. 
Similarly, the investigator/treating physician and/or Sponsor will be free to withdraw 
the patient at any time for safety or administrative reasons. Any other requirements 
necessary for the protection of the human rights of the patient will also be explained, 
according to current CFR (21, parts 312D, 50 and 56), ICH (ICH E6 1997) and GCP 
guidelines and the Declaration of Helsinki, 1964 [as amended in Edinburgh (2000)]. 
A copy of the Declaration of Helsinki is provided in Appendix 8. 
 
6.3 Protocol Approval and Amendment 
This study must be approved by an appropriate institutional review board/committee 
as defined by Federal Regulatory Guidelines (Federal Register Vol. 46, No. 17, 
January 27, 1891, Part 56) and the Office of Human Research Protection (45 CFR 
46). Prior to screening any patients for participation into this study, the 
investigator/treating physician must obtain and provide written documentation of IRB 
review and approval of the protocol and the informed consent document to study 
sponsor. 
The IRB must also be informed of any protocol amendments prior to implementation. 
The investigator/treating physician must provide reports of any change in research 
activity (e.g. the completion, termination or discontinuation of the study) to the IRB.  
 
6.4 Subject Confidentiality and Data Protection 
Signed consent forms for each subject will be coded with the subject’s unique study 


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identification number and stored locally at the clinical site. Authorization to use the 
participant’s health information will be obtained under the requirements of the federal 
Health Insurance Portability and Accountability Act (HIPAA). The Authorization will 
be obtained as part of the informed consent process and will give permission to use 
health information obtained as part of this research study. The participant may 
contact us in writing at any time to withdraw their HIPAA authorization, at which point 
we will not use or provide any health information to researchers and will break the 
link between the participant’s samples and their health information. 
Every effort will be made to maintain the confidentiality of information obtained about 
study participants, however this cannot be guaranteed. Other people may need to 
see the information. While they will normally maintain the confidentiality of the 
information, they may not be required to do so by law. 
Health information will be used to conduct this study, to determine research results, 
and possibly develop new tests, procedures, treatments and commercial products. 
Health information is used to report results of research to federal regulatory 
agencies. Health information from study participants may be included in an audit to 
ensure that the study follows regulations, policies, and study plans. To meet 
regulations, and for reasons related to this research, a copy of informed consent 
forms and records that identify the study participant may be shared with the following: 
the Department of Health and Human Services (DHHS); the Food and Drug 
Administration (FDA); Avera (including physicians, phlebotomists, research staff, 
data managers, and other associated personnel); and Avera Institutional Review 
Boards (IRB). All Avera studies will be subject to audit by Avera and/or the DHHS. 
All records will be maintained indefinitely unless we receive a written request from 
the participant or their legally authorized representative requesting that we remove 
the participant from the study. If informed consent is revoked, we will destroy any 
samples remaining in the laboratory and remove medical information from the 
database. Names, birthdates and medical record numbers may be kept to provide a 
record of past enrollment but all medical record information and other PHI will be 
deleted. Samples and health information that may have been distributed to 
researchers prior to receiving the request to withdrawal may continue to be used by 
the researcher to complete their studies. 
 
6.5 Data Quality Assurance 
CRFs will be used to collect the data, and Avera Health will carry out all data 
management activities. The investigator/treating physician is responsible for 
maintaining accurate, complete and up-to-date records for each patient. The 
investigator/treating physician is also responsible for maintaining all source 
documentation related to the study. All CRFs should be completed in a neat, legible 
manner to ensure accurate interpretation of the data.  
 
6.6 Access to Source Documents 
It is understood that a Clinical Principal Investigator and Clinical Research Associate 
(CRA) will regularly contact and/or visit the investigator/treating physician, and that 
the investigator/treating physician (when requested) will allow the CRA to inspect the 


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study records (CRFs and other pertinent data) and compare patients’ medical records 
with entries in the CRF, provided that patient confidentiality is maintained in 
accordance with local requirements. 
The monitoring and source verification for this study may be conducted remotely and 
the investigator/treating physician will be required to provide source documents and 
case report forms via a secure eFax line for this purpose. It will be the CRA's 
responsibility to inspect the CRFs at regular intervals throughout the study, to verify 
the adherence to the protocol and the completeness, consistency and accuracy of 
the data on the CRF form. The CRA will monitor the study by comparing patients’ 
medical records with entries in the CRF. The CRA must have access to patient 
records that are needed to verify the entries on the CRF. By agreeing to participate 
in this research study, the investigator/treating physician agrees to cooperate with 
the CRA to ensure that any problems detected in the course of the monitoring visits 
are resolved. 
These records and other relevant data may also be reviewed by appropriate qualified 
personnel independent from the CRA appointed to audit the study, and by regulatory 
authorities. Details will remain confidential and patients’ names will not be revealed. 
 
6.7 Study Monitoring 
It is understood that a Clinical Principal Investigator and Clinical Research Associate 
(CRA) will regularly contact and/or visit the investigator/treating physician, and that 
the investigator/treating physician (when requested) will allow the CRA to inspect the 
study records (CRFs and other pertinent data) and compare patients’ medical records 
with entries in the CRF, provided that patient confidentiality is maintained in 
accordance with local requirements. 
The monitoring and source verification for this study will be conducted remotely and 
the investigator/treating physician will be required to provide source documents and 
case report forms via a secure eFax line for this purpose. It will be the CRA's 
responsibility to inspect the CRFs at regular intervals throughout the study, to verify 
the adherence to the protocol and the completeness, consistency and accuracy of 
the data on the CRF form. The CRA will monitor the study by comparing patients’ 
medical records with entries in the CRF. The CRA must have access to patient 
records that are needed to verify the entries on the CRF. By agreeing to participate 
in this research study, the investigator/treating physician agrees to cooperate with 
the CRA to ensure that any problems detected in the course of the monitoring visits 
are resolved. 
These records and other relevant data may also be reviewed by appropriate qualified 
personnel independent from the CRA appointed to audit the study, and by regulatory 
authorities. Details will remain confidential and patients’ names will not be revealed. 
 
 


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6.8 Reporting Product Quality 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 Institution or 
qualified designee to GSK within 1 working day of first becoming aware of the 
possible defect to GSK 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. 
 
6.9 Reporting Adverse Events 
 
6.9.1 Recording of Adverse Events 
An Adverse Event (AE) is any unfavorable and unintended sign (including an abnormal 
laboratory finding), symptom, or disease temporally associated with the use of a 
medical treatment or procedure that may or may not be considered related to the 
medical treatment or procedure. AEs will be collected from the time of informed 
consent to 30 days after last study drug administration. AEs that occur before the 
first study drug administration, concomitant illnesses, which existed before study 
entry, but did not worsen during the treatment period and any pre-existing 
conditions are known as “pre-treatment AEs” and by definition are “unrelated” to 
study drug. All AEs, regardless of the source of identification (e.g., physical 
examination, laboratory assessment, electrocardiograms [ECG], reported by patient), 
must be documented. 
The event of disease progression is an efficacy criterion and is therefore not 
considered an AE. If AEs/SAEs occur in relation to disease progression, the 
AEs/SAEs must be reported per AE/SAE reporting requirements described in 6.11.3, 
6.11.5 and 6.11.7. 
Signs, symptoms, or the clinical sequelae of a suspected overdose of either study 
intervention or a concomitant medication. Overdose per se will not be reported as an 
AE/SAE unless it is an intentional overdose taken with possible suicidal/self-harming 
intent. Such overdoses should be reported regardless of sequelae. 
6.9.2 Assessment of Adverse Events 
Each AE will be assessed by the Investigator with regard to the following categories: 
• Seriousness 
• Intensity 
• Causality 
Seriousness and causality should be assessed in accordance with the International 
Conference on Harmonization’s Technical Requirements for Clinical Safety Data 
Management (E2A Guidelines). Intensity should be assessed in accordance with the 


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Common Terminology Criteria for Adverse Events (CTCAE v.4) 
 
6.9.3 Reporting Serious Adverse Events (SAEs) 
A serious adverse event means that the patient is at immediate risk of death at the 
time of the event; it does not mean that the event hypothetically might have caused 
death if it were more severe. A serious AE (SAE) is defined as any untoward medical 
occurrence that at any dose: 
• Results in death 
• Is life-threatening 
• Requires inpatient hospitalization or prolongation of existing hospitalization 
• Results in persistent or significant disability or incapacity 
• Is a congenital anomaly or birth defect 
• Is an important medical event(s) 
Exception: Planned hospitalization (e.g., for observation, protocol compliance, 
elective procedures, social reasons, etc.) will not be considered an SAE; however, 
any AE that prolongs hospitalization will be considered an SAE. Planned 
hospitalizations should be captured in medical history. 
An important medical event may not be immediately life-threatening or result in 
death or hospitalization, but may jeopardize the patient or require intervention to 
prevent one of the above outcomes. Examples of such events are intensive 
treatment in an emergency room or at home for allergic bronchospasm; blood 
dyscrasias or convulsions that do not result in hospitalization; or development of 
drug dependency or drug abuse. 
Investigators must report to the Institution any AE occurring after the signing of 
informed consent until 30 days following last study drug treatment and within 24 hours 
of becoming aware of the event. 
 
Sponsor AE and Pregnancy Reporting Information 
Dr. Casey Williams 
Fax: +1-605-322-3299 
Telephone: + 1-605-322-3588 
Avera Institutional Review Board (IRB) Telephone: +1-605-322-4706 
All AEs will be recorded from signing of informed consent until 30 days following 
study treatment discontinuation. Serious adverse events occurring after this 30-day 
period and coming to the attention of the Investigator must be reported only if they 
are considered (in the opinion of the Investigator) causally related to the 
investigational drug. 
 
6.9.4 
Follow-up of Adverse Events 


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All AEs experienced by a patient, irrespective of the suspected causality, will be 
monitored until the AE or SAE has resolved, any abnormal laboratory values have 
returned to baseline or stabilized at a level acceptable to the Investigator, until 
there is a satisfactory explanation for the changes observed, until the patient is lost 
to follow-up, or until the patient has died. 
 
6.9.5 
Adverse Events of Special Interest (AESI) for Niraparib 
An Adverse Event 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 to the Sponsor Institution and to GSK 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  
GSK requires only serious AESI to be reported from Investigator-sponsored studies 
(ISS).  Report serious AESI on SAE Report Forms, as follows: 
• MDS and AML along with other secondary cancers should be reported to the 
Sponsor Institution and to GSK upon awareness for any patient who has 
received niraparib (regardless of the timeframe since the last dose).   
• Pneumonitis should be reported to the Sponsor and to GSK through 90 days 
after the last dose 
6.9.6 
Suspected Unexpected Serious Adverse Reactions (SUSARs) 
Per regulatory requirements, if an event is assessed by the Sponsor as a Serious 
Unexpected Adverse Reaction (SUSAR), it is the responsibility of the Sponsor to 
submit the SUSAR to Regulatory Authorities according to applicable regulations. 
In addition, the SUSAR will be distributed to the Investigators/sites utilizing a Council for 
International Organizations of Medical Sciences (CIOMS) report form, or the MedWatch 
3500A form). The Investigator/site will submit a copy of the report to their respective 
Institutional Review Board (IRB) or Independent Ethics Committee (IEC) and GSK per 
the governing institutional requirements and in compliance with local laws and 
guidelines. 
 
6.9.7 
Pregnancy 
The Sponsor has the responsibility to monitor the outcome of all pregnancies reported 
during the Investigator Sponsored Trial. 
The Sponsor must report all pregnancies associated with GSK product including follow 
up outcomes to GSK within 24 hours of awareness.  
Each pregnancy must be reported on an Initial Pregnancy Report 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.  


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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 Institution and GSK within 24 hours. Hospitalization for normal delivery of a healthy newborn 
should not be considered an SAE.  
6.9.8 
Sponsor SAE and Pregnancy Reporting to GSK 
The Sponsor Institution must report all SAEs and all follow up information to GSK on a 
GSK-specific SAE Report Form with accompanying coversheet within 24 hours of 
becoming aware of the initial event or clinically significant follow-up information.  
The Sponsor must provide a causality assessment and must sign and date all SAE 
Report Forms. 
GSK SAE, Serious AESI, and Pregnancy Reporting Information 
 
Send all CIOMS/MedWatch to both: 
Email: OAX37649@gsk.com 
Fax: +44(0) 208754 7822 
 
6.10 Investigational Product 
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. 
 
6.10.1 Dispensing 
The investigator agrees that study drug(s) will be dispensed by the investigator or 
sub-investigator(s) named on the Investigator Agreement or their qualified designees. 
The investigator, sub-investigators, or qualified designees also agree that the study 
drug(s) will be dispensed only to study subjects who have provided written informed 
consent and have met all entry criteria and in accordance with the instructions 
provided in the pharmacy manual. 
 
6.10.2 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 the enrollment number, 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 


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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’s directions. The pharmacist will dispense study treatment for 
each patient according to the protocol and Pharmacy Manual, if applicable. 
 
6.11 Publications 
Manuscript submission for publication of the results of this study, or any aspect of 
work directly related to the study, will be decided by the investigators. Any 
investigator can submit a publication concept proposal including proposed authorship 
order to the rest of the investigators for review, which will take place within 30 
days after a proposal has been submitted. 


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7 SCHEDULE OF EVENTS 
Table 5. Schedule of Study Assessments 
Study Procedures Cycle 
Screening 
Visit 
Cycle 1 
Cycle 2 
Subsequent 
Cycles 
EOT 
Post- 
Treatment 
Assessme
Day 
(≤28 days) 
1 
8 
15 
22 
1 
8 
15 22 
1 
Within 7 
days of 
last dose 
Every 8 
weeks 
Screening 
 
 
 
 
 
 
 
Written informed consent 
X 
 
 
 
 
 
 
Inclusion/Exclusion Criteria 
X 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
Height & Weight 
X 
 
 
 
 
 
 
Vital Signsi 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
ECOG Performance Statusa 
X 
X 
 
 
 
X 
 
 
 
X 
 
 
Medical History & Previous Medications 
X 
 
 
 
 
 
 
Physical Exam 
 
X 
X 
X 
X 
X 
 
 
 
X 
 
 
Concomitant medications 
X 
X 
 
 
 
X 
 
 
 
X 
 
 
Pregnancy Testingb 
X 
 
 
 
 
 
 
Labsd including CBC, BUN and creatinine 
Xc 
X 
X 
X 
X 
X 
 
 
 
X 
 
 
Lipid panel 
X 
 
 
 
 
X 
 
Sample collection (whole blood) for molecular 
and cytogenetic analysise 
X 
 
 
 
 
X 
 
Molecular testing (FoundationOne, CTCs, cfDNA 
if applicablef 
 
 
 
 
 
 
 
Tumor Assessment 
X 
 
 
 
 
After 8 wks and 16 
wks of treatment 
Every 2-3 
cycles 
 
 
Treatment 
 
 
 
 
 
 
 
Adverse Event Monitoring 
 
X 
X 
X 
X 
X 
 
 
 
X 
X 
Xg 
TRSC and HRQOL-LASA 
 
X 
 
 
 
X 
 
 
 
X 
X 
 
Follow-up 
 
 
 
 
 
 
 
Survival assessment 
 
 
 
 
 
 
X 
Follow-up for MDS/AML 
 
 
 
 
X 
Bone marrow aspirate/biopsy 
 
Xh 
 
 


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Footnotes: 
a. Performance Status 0-1 (see Appendix 1 – Performance Status). 
b. Female subjects of childbearing potential must have a serum beta-hCG pregnancy test that will be performed locally within 3 days 
prior to study drug administration. 
c. Laboratory evaluation at the screening visit must be conducted within 7 days prior to study drug administration. 
d. Labs include absolute neutrophil count, platelets, hemoglobin, serum creatinine, total bilirubin, aspartate aminotransferase and alanine 
aminotransferase. 
e. Blood samples collected at screening and EOT will be stored for evaluation if the Sponsor's Medical Monitor finds evaluation necessary 
for assessing niraparib-related risk for MDS/AML (e.g., the patient develops MDS/AML). Mutation profile before and after study 
treatment will be compared to determine whether any mutations were present prior to study treatment. 
f. Molecular testing can take place at any time during the study if applicable. Tests will be commercial (not paid for by study) and are not 
required to participate in the study. 
g. AE should be monitored for 30 days after last dose. 
h. For any patient diagnosed with MDS/AML while on study, a local hematologist must complete a bone marrow aspirate/biopsy. A whole 
blood sample will also be collected for cytogenetic analysis (mutations of select myeloid- associated genes). Testing completed as part of 
standard of care is sufficient as long as the site receives the local 
hematologist’s report. The study site must receive a copy of the 
hematologist's report of aspirate/biopsy findings (which must include a classification according to WHO criteria) and other sample 
testing results related to MDS/AML. 
i. For Cycle 2, weekly blood pressure monitoring may occur remotely. 


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8 REFERENCES 
 
1. 
Lopez J, Banerjee S, Kaye SB. New developments in the treatment of ovarian cancer--future 
perspectives. Annals of oncology: official journal of the European Society for Medical 
Oncology / ESMO. 2013;24 Suppl 10:x69-x76. 
2. 
Despierre E, Yesilyurt BT, Lambrechts S, et al. Epithelial ovarian cancer: rationale for 
changing the one-fits-all standard treatment regimen to subtype-specific treatment. 
International journal of gynecological cancer : official journal of the International Gynecological 
Cancer Society. 2014;24(3):468-477. 
3. 
Pene  F,  Courtine  E,  Cariou  A,  Mira  JP.  Toward  theragnostics.  Critical  care  medicine. 
2009;37(1 Suppl):S50-58. 
4. 
Group USCSW. United States Cancer Statistics: 1999–2011 Incidence and Mortality Web- 
based Report. 2014; http://www.cdc.gov/uscs. Accessed December 2, 2014. 
5. 
De Angelis R, Sant M, Coleman MP, et al. Cancer survival in Europe 1999-2007 by country 
and age: results of EUROCARE--5-a population-based study. The lancet oncology. 
2014;15(1):23-34. 
6. 
Jemal A, Clegg LX, Ward E, et al. Annual report to the nation on the status of cancer, 1975- 
2001, with a special feature regarding survival. Cancer. 2004;101(1):3-27. 
7. 
Siegel RL, Miller KD, Jemal A. Cancer statistics, 2016. CA: a cancer journal for clinicians. 
2016;66(1):7-30. 
8. 
Winer E, Gralow J, Diller L, et al. Clinical cancer advances 2008: major research advances 
in cancer treatment, prevention, and screening--a report from the American Society of 
Clinical Oncology. Journal of clinical oncology: official journal of the American Society of 
Clinical Oncology. 2009;27(5):812-826. 
9. 
Heuson JC. Current overview of EORTC clinical trials with tamoxifen. Cancer treatment 
reports. 1976;60(10):1463-1466. 
10. 
Mouridsen H, Palshof T, Patterson J, Battersby L. Tamoxifen in advanced breast cancer. 
Cancer treatment reviews. 1978;5(3):131-141. 
11. 
Goldstein LJ, Gray R, Badve S, et al. Prognostic utility of the 21-gene assay in hormone 
receptor-positive operable breast cancer compared with classical clinicopathologic features. 
Journal of clinical oncology: official journal of the American Society of Clinical Oncology. 
2008;26(25):4063-4071. 
12. 
Sparano JA, Paik S. Development of the 21-gene assay and its application in clinical 
practice and clinical trials. Journal of clinical oncology: official journal of the American 
Society of Clinical Oncology. 2008;26(5):721-728. 
13. 
Harvey JM, Clark GM, Osborne CK, Allred DC. Estrogen receptor status by 
immunohistochemistry is superior to the ligand-binding assay for predicting response to 
adjuvant endocrine therapy in breast cancer. Journal of clinical oncology: official journal of 
the American Society of Clinical Oncology. 1999;17(5):1474-1481. 
14. 
Bergh J, Jonsson PE, Glimelius B, Nygren P, Care SB-gSCoTAiH. A systematic overview of 
chemotherapy effects in breast cancer. Acta oncologica. 2001;40(2-3):253-281. 
15. 
Fossati R, Confalonieri C, Torri V, et al. Cytotoxic and hormonal treatment for metastatic 
breast cancer: a systematic review of published randomized trials involving 31,510 women. 
Journal of clinical oncology: official journal of the American Society of Clinical Oncology. 
1998;16(10):3439-3460. 
16. 
Siegel R, Naishadham D, Jemal A. Cancer statistics, 2012. CA: a cancer journal for clinicians. 
2012;62(1):10-29. 
17. 
Vyas S, Chang P.  New PARP targets for cancer therapy.  Nature reviews Cancer. 


NIRAPARIB 
CONFIDENTIAL & PROPRIETARY 
PROTOCOL [TNE001] Amendment 31-Aug-2020 
 
47 
2014;14(7):502-509. 
 
18. 
Jagtap P, Szabo C. Poly(ADP-ribose) polymerase and the therapeutic effects of its 
inhibitors. Nature reviews Drug discovery. 2005;4(5):421-440. 
19. 
Jalal S, Earley JN, Turchi JJ. DNA repair: from genome maintenance to biomarker and 
therapeutic target. Clinical cancer research: an official journal of the American Association 
for Cancer Research. 2011;17(22):6973-6984. 
20. 
Narod SA, Foulkes WD. BRCA1 and BRCA2: 1994 and beyond. Nature reviews Cancer. 
2004;4(9):665-676. 
21. 
Turner N, Tutt A, Ashworth A. Hallmarks of 'BRCAness' in sporadic cancers. Nature reviews 
Cancer. 2004;4(10):814-819. 
22. 
Cancer Genome Atlas Research N. Integrated genomic analyses of ovarian carcinoma. 
Nature. 2011;474(7353):609-615. 
23. 
Nijman  SM,  Friend  SH.  Cancer.  Potential  of  the  synthetic  lethality  principle.  Science. 
2013;342(6160):809-811. 
24. 
Jones P, Wilcoxen K, Rowley M, Toniatti C. Niraparib: A Poly(ADP-ribose) Polymerase 
(PARP) Inhibitor for the Treatment of Tumors with Defective Homologous Recombination. 
Journal of medicinal chemistry. 2015;58(8):3302-3314. 
25. 
Daemen A, Wolf DM, Korkola JE, et al. Cross-platform pathway-based analysis identifies 
markers of response to the PARP inhibitor olaparib. Breast cancer research and treatment. 
2012;135(2):505-517. 
26. 
Kumar A, Fernandez-Capetillo O, Carrera AC. Nuclear phosphoinositide 3-kinase beta 
controls double-strand break DNA repair. Proceedings of the National Academy of Sciences 
of the United States of America. 2010;107(16):7491-7496. 
27. 
Beuvink I, Boulay A, Fumagalli S, et al. The mTOR inhibitor RAD001 sensitizes tumor cells 
to DNA-damaged induced apoptosis through inhibition of p21 translation. Cell. 
2005;120(6):747-759. 
28. 
Keith CT, Schreiber SL. PIK-related kinases: DNA repair, recombination, and cell cycle 
checkpoints. Science. 1995;270(5233):50-51. 
29. 
De P, Sun Y, Carlson JH, Friedman LS, Leyland-Jones BR, Dey N. Doubling down on the 
PI3K-AKT-mTOR pathway enhances the antitumor efficacy of PARP inhibitor in triple 
negative breast cancer model beyond BRCA-ness. Neoplasia. 2014;16(1):43-72. 
30. 
De Summa S, Pinto R, Sambiasi D, et al. BRCAness: a deeper insight into basal-like breast 
tumors. Annals of oncology : official journal of the European Society for Medical Oncology / 
ESMO. 2013;24 Suppl 8:viii13-viii21. 
31. 
Juvekar A, Burga LN, Hu H, et al. Combining a PI3K inhibitor with a PARP inhibitor provides 
an effective therapy for BRCA1-related breast cancer. Cancer Discov. 2012;2(11):1048- 
1063. 
32. 
Ibrahim YH, Garcia-Garcia C, Serra V, et al. PI3K inhibition impairs BRCA1/2 expression 
and sensitizes BRCA-proficient triple-negative breast cancer to PARP inhibition. Cancer 
Discov. 2012;2(11):1036-1047. 
33. 
De P, Miskimins K, Dey N, Leyland-Jones B. Promise of rapalogues versus mTOR kinase 
inhibitors in subset specific breast cancer: old targets new hope. Cancer treatment reviews. 
2013;39(5):403-412. 
34. 
Dennis PB, Jaeschke A, Saitoh M, Fowler B, Kozma SC, Thomas G. Mammalian TOR: a 
homeostatic ATP sensor. Science. 2001;294(5544):1102-1105. 
35. 
Hay N, Sonenberg N. Upstream and downstream of mTOR. Genes Dev. 2004;18(16):1926- 
1945. 
36. 
Vardiman JW. The World Health Organization (WHO) classification of tumors of the 


NIRAPARIB 
CONFIDENTIAL & PROPRIETARY 
PROTOCOL [TNE001] Amendment 31-Aug-2020 
 
48 
hematopoietic and lymphoid tissues: an overview with emphasis on the myeloid neoplasms. 
Chem Biol Interact. 2010;184(1-2):16-20. 
37. 
Schiffer CA, Anderson KC, Bennett CL, et al. Platelet transfusion for patients with cancer: 
clinical practice guidelines of the American Society of Clinical Oncology. Journal of clinical 
oncology : official journal of the American Society of Clinical Oncology. 2001;19(5):1519- 
1538. 
38. 
Slichter SJ. Evidence-based platelet transfusion guidelines. Hematology Am Soc Hematol 
Educ Program. 2007:172-178. 
39. 
Rustin GJ, Vergote I, Eisenhauer E, et al. Definitions for response and progression in 
ovarian cancer clinical trials incorporating RECIST 1.1 and CA 125 agreed by the 
Gynecological Cancer Intergroup (GCIG). International journal of gynecological cancer : 
official journal of the International Gynecological Cancer Society. 2011;21(2):419-423. 


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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 
selfcare 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 selfcare; 
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 selfcare; 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 – INTERACTION WITH OTHER MEDICINAL 
PRODUCTS AND OTHER FORMS OF INTERACTION 
 
Pharmacodynamic interactions 
The combination of niraparib with vaccines or immunosuppressant agents has not 
been studied. 
The data on niraparib in combination with cytotoxic medicinal products are limited. 
Therefore, caution should be taken if niraparib is used in combination with other 
cytotoxic medicinal products. 
Pharmacokinetic interactions 
Effect of other drugs on niraparib 
 
Substrate of CYPs (CYPA2 and CYP3A4) 
Niraparib is a substrate of carboxylesterases (CEs) and UDP-
glucuronosyltransferases (UGTs) in vivo. Oxidative metabolism of niraparib is 
minimal in vivo. No dose adjustment for niraparib is required when administered 
concomitantly with drugs known to inhibit or induce CYP enzymes. 
 
Substrate of efflux transporters (P-gp, BCRP, and BESP) 
Niraparib is a substrate of P-glycoprotein (P-gp) and Breast Cancer Resistance 
Protein (BCRP). 
Niraparib is not a substrate of bile salt export pump (BSEP). The major primary 
metabolite M1 is not a substrate of P-gp, BCRP, or BESP. No dose adjustment for 
niraparib is required when administered concomitantly with drugs known to 
inhibitors of P-gp, BCRP, and BESP efflux transporters. 
 
Substrate of hepatic uptake transporters (OATP1B1, OATP1B3, and OCT1) 
Neither niraparib nor M1 is a substrate of organic anion transport polypeptide 1B1 
(OATP1B1), 1B3 (OATP1B3), or organic cation transporter 1 (OCT1). No dose 
adjustment for niraparib is required when administered concomitantly with drugs 
known to inhibitors of OATP1B1, OATP1B3, and OCT1 uptake transporters. 
 
Substrate of renal uptake transporters (OAT1, OAT3, and OCT2) 
Neither niraparib nor M1 is a substrate of organic anion transporter 1 (OAT1), 3 
(OAT3), and organic cation transporter 2 (OCT2). No dose adjustment for niraparib 
is required when administered concomitantly with drugs known to inhibitors of 
OAT1, OAT3, and OCT2 uptake transporters. 
 
Effect of niraparib on other drugs 
Inhibition of CYPs (CYPA2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, and 
CYP3A4) 


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Neither niraparib nor M1 is an inhibitor of any drug-metabolising CYP enzymes, 
namely CYPA2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, and CYP3A4. 
 
Induction of CYPs (CYPA2 and CYP3A4) 
Neither niraparib nor M1 is a CYP3A4 inducer. Niraparib weakly induces CYP1A2 in 
vitro. However, a clinically meaningful drug interaction via an induction of CYP3A4 
or CYP1A2 is unlikely. M1 is not a CYP1A2 inducer. 
 
Inhibition of efflux transporters (P-gp, BCRP, and BESP) 
Niraparib is not an inhibitor of P-gp or BSEP. Niraparib is a weak inhibitor of BCRP in 
vitro. However, a clinically meaningful drug interaction via an inhibition of BCRP is 
unlikely. The major primary metabolite M1 does not appear to be an inhibitor of P-
gp, BCRP, or BESP. 
 
Inhibition of hepatic uptake transporters (OATP1B1, OATP1B3, and OCT1) 
Neither niraparib nor M1 is an inhibitor of organic anion transport polypeptide 1B1 
(OATP1B1), 1B3 (OATP1B3), or organic cation transporter 1 (OCT1). 
 
Inhibition of renal uptake transporters (OAT1, OAT3, and OCT2) 
Neither niraparib nor M1 is an inhibitor of organic anion transporter 1 (OAT1), 3 
(OAT3), and organic cation transporter 2 (OCT2). 
 
Moderate CYP3A4 Inhibitors 
amprenavir 
darunavir/ritonavir 
fosamprenavir 
aprepitant 
diltiazem 
grapefruit juice (a) 
atazanavir 
erythromycin 
imatinib 
ciprofloxacin 
fluconazole 
verapamil 
Strong CYP3A4 Inhibitors 
boceprevir 
ketoconazole 
ritonavir 
clarithromycin 
lopinavir/ritonavir 
saquinavir 
conivaptan 
mibefradil (b) 
telaprevir 
grapefruit juice (a) 
nefazodone 
telithromycin 
indinavir 
nelfinavir 
voriconazole 
itraconazole 
posaconazole 
Clinically Significant Enzyme Inducers 
carbamazepine 
rifabutin 
St. Johns Wort 
phenobarbital 
rifampin 
phenytoin 
rifapentine 
 
Source: 
fda.gov/Drugs/DevelopmentApprovalProcess/DevelopmentResources/DrugInteractionsLabeling/ucm093664.html


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APPENDIX 3 – CRITERIA FOR PROGRESSIVE DISEASE 
 
Adapted from: Revised Response Evaluation Criteria in Solid Tumors (RECIST) 
Criteria; Version 1.1, 200927 
All subjects who have received a minimum of 2 cycles of study treatment will be 
considered evaluable for response. All subjects who develop early progressive disease 
(regardless of the duration of the study treatment) prior to response evaluation will be 
considered to have progressed on study. 
 
Assessment of Overall Tumor Burden and Measurable Disease 
To assess objective response, it is necessary to estimate the overall tumor burden at 
baseline and use this as a comparator for subsequent measurements. Only subjects 
with measurable disease at baseline should be included in protocols where objective 
tumor response is a primary endpoint. Measurable disease is defined by the presence 
of at least one measurable lesion. 
A measurable lesion is defined as a lesion that can be accurately measured by CT scan 
in at least one dimension (longest diameter to be recorded) 
as ≥ 10 mm. If the 
measurable disease is restricted to a solitary lesion, its neoplastic nature should be 
confirmed by cytology/histology. A tumor lesion that is situated in a previously irradiated 
area is eligible for measurable disease provided: 1) there has been documented disease 
progression in this site; 2) the criteria for measurability as outlined above are met; 3) it 
is not the only site of measurable disease. 
Lesions that are considered non-measurable include bone lesions, leptomeningeal 
disease, ascites, pleural/pericardial effusion, lymphangitis 
cutis/pulmonis, and 
abdominal masses that are not confirmed and followed by imaging techniques. 
Previously irradiated lesions will be considered non-measurable except in cases of 
documented progression of the lesion since the completion of radiation therapy. 
 
Baseline Documentation of Target and Non-Target Lesions 
Baseline documentation of tumor sites may include imaging assessment of disease in 
the chest, abdomen, and pelvis. A baseline imaging study of the brain is not required 
unless there is a prior history of brain metastasis or the subject has neurological 
symptoms. All baseline tumor measurements must be documented within 1 month prior 
to start of therapy. Repeat tumor measurements will be required after every 2 cycles of 
study? Or after 3 cycles of therapy? If there is reduction in tumor size consistent with a 
complete response (CR) or a partial response (PR), or stabilization in the tumor size 
consistent with stable disease (SD), tumor evaluation will be repeated in 4 weeks to allow 
for confirmation of the tumor status (changed from response). Subsequent tumor 
evaluations will then be performed after every 2 cycles. 
 
 


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Target Lesions 
All measurable lesions (up to a maximum of 5 lesions in total and a maximum of 2 lesions 
per organ) representative of all involved organs should be identified as target lesions and 
recorded and measured at baseline. Target lesions should be selected on the basis of 
their size (lesions with the longest diameter and their suitability for accurate repetitive 
measurements (either imaging techniques or clinically). A sum of the longest diameter 
(LD) for all target lesions will be calculated and reported as the baseline sum LD. The 
baseline sum LD will be used as reference to further characterize the objective tumor 
response of the measurable dimension of the disease. 
 
Non-Target Lesions 
All other lesions (or sites of disease) should be identified as non-target lesions and should 
also be recorded at baseline. Measurements are not required and these lesions should 
be followed as “present”, “absent”, “increased”, or “decreased.” 
 
Tumor Response Criteria 
 
Evaluation of Target Lesions 
Complete response (CR): Disappearance of all target lesions. Must be confirmed by 
repeat studies that should be performed no less than 4 weeks after the criteria for 
response are first met. 
 
Partial response 
(PR): 
At least a 30% decrease in the sum of diameters of target 
lesions, taking as reference the baseline sum diameters. 
Must be confirmed by repeat studies that should be 
performed no less than 4 weeks after the criteria for 
response are first met. 
Progression (PD): 
At least a 20% increase in the sum of diameters of target 
lesions, taking as references 
the smallest sum of 
diameters recorded since the treatment started (and the 
sum must demonstrate an absolute increase of at least 5 
mm) or the appearance of one or more new lesions. 
Stable disease 
(SD): 
Neither sufficient shrinkage to qualify for PR nor sufficient 
increase to qualify for PD, taking as references the 
smallest sum of diameters since the treatment started. 
Must be confirmed by repeat studies that should be 
performed no less than 4 weeks after the criteria for stable 
disease are first met. 
 
 
 


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Evaluation of Non-target Lesions 
Complete 
response 
(CR): 
Disappearance of all non-target lesions and normalization of 
tumor marker levels. All lymph nodes must be non-
pathological in size (<10 mm short axis) 
Non-complete 
response (non-
CR): 
Persistence of one or more non-target lesions and/or 
maintenance of tumor marker level above the normal limits. 
Progression (PD): 
Appearance of one or more new lesions. Unequivocal 
progression of existing non-target lesions.* 
*Although a clear progression of “non-target” lesions only is exceptional, in such 
circumstances, the opinion of the treating physician should prevail and the 
progression status should be confirmed later on by the review panel (or study chair). 
Note: If tumor markers are initially above the ULN, they must normalize for that subject 
to be considered in CR. 
If measurable disease is restricted to a solitary lesion, its neoplastic nature should be 
confirmed by cytology or histology. In rare cases, such techniques can be used to 
differentiate between PR and CR (i.e., residual lesions in tumor types such as germ cell 
tumors, where known residual benign tumors may remain). 
Cytological confirmation of the neoplastic origin of any effusion that appears or worsens 
during treatment, when the measurable tumor has met criteria for response or stable 
disease, is mandatory to differentiate between response or stable disease and 
progressive disease (an effusion may be a side effect of the treatment). 
 
Evaluation of Best Overall Response 
The best overall response is the best response recorded from the start of the treatment 
until disease progression/recurrence (taking as reference for progressive disease the 
smallest measurements recorded since the treatment started). In general the subject’s 
best response assignment will depend on the achievement of both measurement and 
confirmation criteria. 
 
DETERMINATION OF BEST OVERALL RESPONSE 
Target Lesions 
Non-Target 
Lesions 
New Lesions Overall Response 
CR 
CR 
No 
CR 
CR 
Non-CR/Non-PD 
No 
PR 
PR 
Non-PD 
No 
PR 
SD 
Non-PD 
No 
SD 
PD 
Any 
Yes or No 
PD 
Any 
PD 
Yes or No 
PD 
Any 
Any 
Yes 
PD 


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Note: Subjects with a global deterioration of health status, requiring discontinuation of 
treatment without objective evidence of disease progression at that time, should be 
reported as “symptomatic deterioration.” Every effort should be made to document the 
objective progression, even after discontinuation of treatment. 
Conditions that may define “early progression, early death, and inevaluability” are study-
specific and should be clearly defined in each protocol (depending on treatment 
duration, treatment periodicity). 
In some circumstances it may be difficult to distinguish residual disease from normal 
tissue. When the evaluation of complete response depends upon this determination, it 
is recommended that the residual lesion be investigated (fine needle aspiration/biopsy), 
before confirming the complete response status. 
 
Guidelines for Evaluation of Measurable Disease 
All measurements should be recorded in metric notation using calipers. All baseline 
evaluations should be performed as close as possible to the treatment start and never 
more than 4 weeks before the beginning of treatment. 
Note: Tumor lesions in a previously irradiated area are not optimally considered 
measurable disease. If the investigator/treating physician thinks it appropriate to include 
them, the conditions under which such lesions should be considered must be defined in 
the protocol. 
The same method of assessment and the same technique should be used to 
characterize each identified and reported lesion at baseline and during follow-up. 
Imaging-based evaluation is preferred to evaluation by clinical examination when both 
methods have been used to assess the antitumor effect of a treatment. 
Clinical lesions will only be considered measurable when they are superficial (e.g., skin 
nodules, palpable lymph nodes). In the case of skin lesions, documentation by color 
photography, including a ruler to estimate size of the lesion, is recommended. 
Lesions on chest radiographs are acceptable as measurable lesions when they are 
clearly defined and surrounded by aerated lung. Computerized tomography (CT) is 
preferable. 
 
Cross-sectional imaging (conventional CT and MRI) should be performed, with 
contiguous cuts ≤ 10 mm in thickness. Spiral CT should be performed using a 5 mm 
contiguous reconstruction algorithm; this applies to the chest, abdomen, and pelvis 
(head, neck, and extremities usually require specific imaging protocols). 
Ultrasound (US) should not be used to measure tumor lesions that are clinically not 
easily accessible, when the primary 
endpoint of a study is objective response 
evaluation. It is a possible alternative to clinical measurement of superficial palpable 
nodes, subcutaneous lesions, and thyroid nodules. US might also be useful to confirm 
complete disappearance of superficial lesions usually assessed by clinical evaluation. 
Confirmatory Measurement/Duration of Response 
To be assigned a status of PR or CR, changes in tumor measurements must be 
confirmed by repeat studies performed no less than 4 weeks after the criteria for 


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response are first met. In the case of SD, follow-up measurements must have met the 
SD criteria at least once after study entry at an interval of 4 weeks. 
 
Duration of Response 
The duration of overall response will be measured from the time measurement criteria 
are met for CR/PR (whichever is first recorded) until the first date that recurrent or 
progressive disease is objectively documented (taking as reference for progressive 
disease the smallest measurements recorded since the treatment started). 
The duration of overall complete response will be measured from the time measurement 
criteria are first met for CR until the first date that recurrent or progressive disease is 
objectively documented. 
 
Duration of Stable Disease 
Stable disease is measured from the start of treatment until criteria for progression are 
met, taking as reference the smallest sum of measurements recorded since the treatment 
started. 
 
Time to Disease Progression 
Defined as the time from the date of enrollment/randomization to date of progression as 
assessed by the conventional response criteria, death, or the start of further antitumor 
therapy. Subjects lost to follow-up will be censored at their last known alive date. 
 
Reporting of results 
• All patients included in the study must be assessed for response to treatment, 
even if there are major protocol treatment deviations or if they are ineligible. 
Each patient will be assigned one of the following categories: 1) complete 
response, 2) partial response, 3) stable disease, 4) progressive disease, 5) early 
death from malignant disease, 6) early death from toxicity, 7) early death 
because of other cause, or 9) unknown (not assessable, insufficient data). 
• All of the patients who met the eligibility criteria should be included in the main 
analysis of the response rate. Patients in response categories 4-9 should be 
considered as failing to respond to treatment (disease progression). Thus, an 
incorrect treatment schedule or drug administration does not result in exclusion 
from the analysis of the response rate. Precise definitions for categories 4-9 will 
be protocol specific. 
• All conclusions should be based on all eligible patients. 
• Subanalyses may then be performed on the basis of a subset of patients, 
excluding those for whom major protocol deviations have been identified (e.g., 
early death due to other reasons, early discontinuation of treatment, major 
protocol violations, etc.). However, these sub- analyses may not serve as the 
basis for drawing conclusions concerning treatment efficacy, and the reasons for 
excluding patients from the analysis should be clearly reported. 
 
The 95% confidence intervals should be provided. 


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Definitions for Response and Progression in Ovarian Cancer Clinical Trials 
Incorporating RECIST 1.1 and CA 125 - Consensus by the Gynecological Cancer 
Intergroup (GCIG) 
The following two scenarios will be accepted for gynecological patients according to the 
GCIG definitions as cited in [34]: 
 
Table 2. Recommendations according to GCIG for CA 125 criteria for response and 
progression [60]. 
Use Recommended by GCIG 
Relapse trials 
CA 125 response and progression 
 
Definition of Response According to CA 125 
At least a 50% reduction in CA 125 levels from the pretreatment sample must be 
achieved in order to be considered a CA 125 response, which must be confirmed 
and maintained for at least 28 days. The pretreatment CA 125 must be at least twice 
the upper limit of the reference range and within 2 weeks before initiating treatment 
in order to evaluate a patient based on this criteria.  Additionally, the following rules will 
apply: 
• If the sample shows a 50% reduction in CA 125 levels, the 28 day confirmatory 
sample must be less than or equal to the previous sample (an assay variability 
of 10% is allowed) 
• Variations within the reference range of CA 125 levels will not interfere with the 
definition of response. 
• The same assay method must be used for each patient, and the assay must 
routinely undergo quality control testing 
• If the patient is receiving a mouse antibody then they are not considered to be 
evaluable by CA 125 unless there is data to support that the assay is not 
influenced by human anti-mouse antibody. 
• If there has been medical or surgical interference with the patient’s pleura or 
peritoneum during the previous 28 days then the patient is not considered to be 
evaluable by CA 125 
• If therapy has included 2 treatment modalities (e.g. surgery and chemotherapy 
and/or targeted therapy) then the CA 125 cannot distinguish between the effects 
of the modalities 
• The date that the CA 125 level is first reduced by 50% will be the date of the CA 
125 response 
 
Definition of Progression According to CA 125 
If non-target lesions are present by radiological imaging, then the following will be used 
to evaluate best overall response 


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Table 3. Evaluation of best overall response in patients without measurable disease 
but are evaluable by CA 125 [60]. 
CA 125 
Nontarget 
Lesions 
New Lesions 
Overall 
Serological 
Response 
Best Response 
Also Requires 
Response and 
normalized 
CR 
No 
CR 
Confirmed and 
maintained for 
at least 28 
Response 
Non-PD 
No 
PR 
 
Normalized but 
no response 
Non-CR/Non-
PD 
No 
SD 
 
Non-PR/non-PD 
Non-PD 
No 
SD 
 
PD 
Any 
Yes or No 
PD 
 
Any 
PD 
Yes or No 
PD 
 
Any 
Any 
Yes 
PD 
 
 
For patients that have measurable disease per RECIST 1.1 and CA 125 criteria, 
responses should be determined according to the following table. 
Table 4. Best overall response combining RECIST 1.1 and CA 125 [60]. 
 
Target Lesion 
Nontarget 
New Lesion 
CA 125 
Overall Best 
Response 
CR 
CR 
No 
Normal 
CR 
CR 
Non-CR, Non-
PD 
No 
Not PD 
PR 
CR 
CR 
No 
PR but not 
PR 
CR 
Not evaluated 
No 
PR 
PR 
PR 
Non-PD or Not 
evaluated 
No 
Not PD 
PR 
Not evaluated 
Non-PD 
No 
PR 
PR 
 
 
PD or new lesion >28 days from CA 125 PR 
PR 
PR 
SD 
Non-PD 
No 
PR 
PR 
SD 
Non-PD or Not 
Evaluated 
No 
Not PR and Not 
PD 
SD 
PD or new lesion ≤28 days from CA 125 PR 
PR 
PD 
PD 
Any 
Yes or No 
Any 
PD 
Any 
PD 
Yes or No 
Any 
PD 
Any 
Any 
Yes 
Any 
PD 
Any 
Any 
Yes or No 
PD 
PD 
If both the RECIST 1.1 and CA 125 response criteria are used, the date of response 
will be defined as the date of the earlier of the two events if combined response reporting 
is to be used. Also, the best response for CR and PR also requires confirmation and 
maintenance for at least 28 days. 
 


NI R A P A RI B  
C O N FI D E N TI A L  & P R O P RI E T A R Y  
P R O T O C OL [ T N E 0 0 1] A m e n d m e nt 3 1 - A u g-2 0 2 0  
 
5 9  
A P P E N DI X  4 – T H E R A P Y -R E L A T E D  S Y M P T O M S  C H E C K LI S T  ( T R S C) 
N a m e:     H o s pit al # D at e:  
P L E A S E  C H E C K  T H E  P R O B L E M S  Y O U  H A V E  H A D  I M M E DI A T E L Y A F T E R  A N D  SI N C E  Y O U R  L A S T  T R E A T M E N T . 
P L E A S E  CI R C L E  H O W  S E V E R E  T H E  P R O B L E M W A S  A C C O R DI N G  T O  T H E  F O L L O WI N G  S C A L E:  
 
0 = N O N E 1 =  MI L D 2  = M O D E R A T E  3 = S E V E R E  4 = V E R Y S E V E R E  
 
C H E C K  
E X A M P L E  
D e gr e e  of S e v erit y  ( CI R C L E)  
 
 
P ai n  
 
0  
1  
2  
  
4  
 
T a st e  C h a n g e  
0  
1  
2  
3  
4  
 
L o s s of a p p etit e  
0  
1  
2  
3  
4  
 
N a u s e a  
0  
1  
2  
3  
4  
 
V o miti n g  
0  
1  
2  
3  
4  
v  
 
W ei g ht l o s s  
0  
1  
2  
3  
4  
 
S or e  m o ut h  
0  
1  
2  
3  
4  
 
C o u g h  
0  
1  
2  
3  
4  
 
S or e  t hr o at 
0  
1  
2  
3  
4  
 
Diffi c ult y  s w all o wi n g  
0  
1  
2  
3  
4  
 
J a w  p ai n  
0  
1  
2  
3  
4  
 
S h ort n e s s  of  br e at h  
0  
1  
2  
3  
4  
 
N u m b n e s s i n fi n g er s a n d/ or t o e s 
0  
1  
2  
3  
4  
 
F e eli n g  sl u g gi s h  
0  
1  
2  
3  
4  
 
D e pr e s si o n  
0  
1  
2  
3  
4  
 
Diffi c ult y  c o n c e ntr ati n g  
0  
1  
2  
3  
4  
 
F e v er  
0  
1  
2  
3  
4  
 
Br ui si n g  
0  
1  
2  
3  
4  
 
Bl e e di n g  
0  
1  
2  
3  
4  
 
H air  l o s s 
0  
1  
2  
3  
4  
 
S ki n  c h a n g e s  
0  
1  
2  
3  
4  
 
S or e n e s s  i n v ei n  w h er e  c h e m ot h er a p y  
w a s  gi v e n  
0  
1  
2  
3  
4  
 
Diffi c ult y  sl e e pi n g  
0  
1  
2  
3  
4  
 
P ai n  
0  
1  
2  
3  
4  
 
D e cr e a s e d  i nt er e st i n s e x u al  a cti vit y  
0  
1  
2  
3  
4  
 
C o n sti p ati o n  
0  
1  
2  
3  
4  
 
Ot h er  pr o bl e m s  ( pl e a s e li st b el o w)  
 
 
 
 
 
 
 
0  
1  
2  
3  
4  
 
 
0  
1  
2  
3  
4  
 
 
0  
1  
2  
3  
4  
 
 
0  
1  
2  
3  
4  
P h o e b e  D.  Willi a m s, P h D  © C o p yri g ht  1 9 9 5  U ni v er sit y  of K a n s a s  M e di c al  C e nt er  


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APPENDIX 5 – WHO MDS CLASSIFICATION CRITERIA 
 
The 2008 World Health Organization (WHO) classification of myelodysplastic 
syndromes (MDS),[1] as well as the International Prognostic Scoring System (IPSS), 
are provided below.[2] 
Myelodysplastic syndromes are a group of clonal myeloid neoplasms characterized 
by ineffective hematopoiesis that present clinically as cytopenia(s), dysplasia in one 
or more hematopoietic cell lines in the bone marrow, and risk of transformation to 
acute myeloid leukemia (AML) 
The WHO classification system of MDS relies on incorporating clinical features, 
peripheral blood and bone marrow findings, and cytogenetic analysis.[1] This 
classification also includes a collection of heterogeneous neoplasms that share 
features of MDS and myeloproliferative neoplasms. 
 
 
Refractory cytopenia with unilineage dysplasia (RCUD): 
Blood: single cytopenia or bicytopenia 
Bone marrow: dysplasia in ≥ 10% of 1 cell line, < 5% blasts 
 
 
Refractory anemia with ring sideroblasts (RARS): 
Blood: anemia, no blasts 
Bone marrow:  ≥  15%  of  erythroid  precursors  with  ring  sideroblasts,  erythroid 
dysplasia only, < 5% blasts 
 
 
Refractory cytopenia with multilineage dysplasia (RCMD): 
Blood: cytopenia(s), < 1 × 10 9/L monocytes 
Bone marrow: dysplasia in ≥ 10% of cells in ≥ 2 hematopoietic lineages, ±15% ring 
sideroblasts, < 5% blasts 
 
 
Refractory anemia with excess blasts-1 (RAEB-1): 
Blood: cytopenia(s) ≥ 2-4% blasts, < 1 × 10 9/L monocytes 
Bone marrow: unilineage or multilineage dysplasia, no Auer rods, 5-9% blasts 
 
 
Refractory anemia with excess blasts-2 (RAEB-2): 
Blood: cytopenia(s), 5-19% blasts, < 1 × 10 9/L monocytes 
Bone marrow: unilineage or multilineage dysplasia, Auer rods, ± 10-19% blasts 
 
 


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Myelodysplastic syndrome – unclassified (MDS-U): 
Blood: cytopenias 
Bone marrow:  unilineage dysplasia or  no  dysplasia  but  characteristic  MDS 
cytogenetics, <5% blasts 
 
 
MDS associated with isolated del(5q): 
Blood: anemia, platelet levels normal or increased 
Bone marrow: unilineage erythroid dysplasia, isolated del(5q), < 5% blasts 
 
 
Therapy-related MDS (t-MDS): 
Blood and bone marrow findings of 1 of the above diagnostic categories (frequently 
with multilineage dysplasia) 
Previous history of exposure to cytotoxic chemotherapy and/or radiation therapy 
administered for treatment of cancer or non-neoplastic disease 
2008 WHO terminology: therapy-related myeloid neoplasm 


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APPENDIX 6 – HEALTH-RELATED QUALITY OF LIFE (HRQOL), 
LINEAR ANALOGUE SELF-ASSESSMENT (LASA) 
Patient Name: 
xxxxxx  
 Date: 
 
 
 
 
Patient Number:   
                               
Directions: Please circle the number (0-10) best reflecting your response to the 
following that describes your feelings during the past week, including today. 
How would you describe: 
1. your overall Quality of Life? 
 
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
As bad as 
As good as 
it can be 
it can be 
 
2. your overall mental (intellectual) well being? 
 
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
As bad as 
As good as 
it can be 
it can be 
 
3. your overall physical well being? 
 
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
As bad as 
As good as 
it can be 
it can be 
 
4. your overall emotional well being? 
 
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
As bad as 
As good as 
it can be 
it can be 
 
5. your level of social activity? 
 
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
As bad as 
As good as 
it can be 
it can be 
6. your overall spiritual well being? 
 
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
As bad as 
As good as 
it can be 
it can be 


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APPENDIX 7 – DECLARATION OF HELSINKI 
 
World Medical Association Declaration of Helsinki Ethical Principles for 
Medical Research Involving Human Subjects 
 
 
Adopted by the 18th WMA General Assembly, Helsinki, Finland, June 1964 and 
amended by the 
29th WMA General Assembly, Tokyo, Japan, October 1975 35th WMA General 
Assembly, Venice, Italy, October 1983 41st WMA General Assembly, Hong Kong, 
September 1989 48th WMA General Assembly, Somerset West, Republic of South 
Africa, October 1996 and the 52nd WMA General Assembly, Edinburgh, Scotland, 
October 2000 
 
A. INTRODUCTION 
1. The World Medical Association has developed the Declaration of Helsinki as 
a statement of ethical principles to provide guidance to physicians and other 
participants in medical research involving human subjects. Medical research 
involving human subjects includes research on identifiable human material or 
identifiable data. 
 
2. It is the duty of the physician to promote and safeguard the health of the 
people. The physician's knowledge and conscience are dedicated to the 
fulfillment of this duty. 
 
3. The Declaration of Geneva of the World Medical Association binds the 
physician with the words, "The health of my patient will be my first 
consideration," and the International Code of Medical Ethics declares that, "A 
physician shall act only in the patient's interest when providing medical care 
which might have the effect of weakening the physical and mental condition of 
the patient." 
 
4. Medical progress is based on research that ultimately must rest in part on 
experimentation involving human subjects. 
 
5. In medical research on human subjects, considerations related to the well- 
being of the human subject should take precedence over the interests of 
science and society. 
 
6. The primary purpose of medical research involving human subjects is to 
improve prophylactic, diagnostic and therapeutic procedures and the 
understanding of the etiology and pathogenesis of disease. Even the best 


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proven prophylactic, diagnostic, and therapeutic methods must continuously 
be challenged through research for their effectiveness, efficiency, accessibility 
and quality. 
 
7. In current medical practice and in medical research, most prophylactic, 
diagnostic and therapeutic procedures involve risks and burdens. 
 
8. Medical research is subject to ethical standards that promote respect for all 
human beings and protect their health and rights. Some research populations 
are vulnerable and need special protection. The particular needs of the 
economically and medically disadvantaged must be recognized. Special 
attention is also required for those who cannot give or refuse consent for 
themselves, for those who may be subject to giving consent under duress, for 
those who will not benefit personally from the research and for those for 
whom the research is combined with care. 
 
9. Research investigators/treating physician should be aware of the ethical, legal 
and regulatory requirements for research on human subjects in their own 
countries as well as applicable international requirements. No national ethical, 
legal or regulatory requirement should be allowed to reduce or eliminate any 
of the protections for human subjects set forth in this Declaration. 
 
B. BASIC PRINCIPLES FOR ALL MEDICAL RESEARCH 
 
1. It is the duty of the physician in medical research to protect the life, health, 
privacy, and dignity of the human subject. 
 
2. Medical research involving human subjects must conform to generally 
accepted scientific principles, be based on a thorough knowledge of the 
scientific literature, other relevant sources of information, and on adequate 
laboratory and, where appropriate, animal experimentation. 
 
3. Appropriate caution must be exercised in the conduct of research which may 
affect the environment, and the welfare of animals used for research must be 
respected. 
 
4. The design and performance of each experimental procedure involving 
human subjects should be clearly formulated in an experimental protocol. 
This protocol should be submitted for consideration, comment, guidance, and 
where appropriate, approval to a specially appointed ethical review committee, 
which must be independent of the investigator/treating physician, the sponsor 
or any other kind of undue influence. This independent committee should 
be in conformity with the laws and regulations of the country in which the 
research experiment is performed. The committee has 


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the right to monitor ongoing trials. The researcher has the obligation to provide 
monitoring information to the committee, especially any serious adverse 
events. The researcher should also submit to the committee, for review, 
information regarding funding, sponsors, institutional affiliations, other potential 
conflicts of interest and incentives for subjects. 
 
5. The research protocol should always contain a statement of the ethical 
considerations involved and should indicate that there is compliance with the 
principles enunciated in this Declaration. 
 
6. Medical research involving human subjects should be conducted only by 
scientifically qualified persons and under the supervision of a clinically 
competent medical person. The responsibility for the human subject must 
always rest with a medically qualified person and never rest on the subject of 
the research, even though the subject has given consent. 
 
7. Every medical research project involving human subjects should be preceded 
by careful assessment of predictable risks and burdens in comparison with 
foreseeable benefits to the subject or to others. This does not preclude the 
participation of healthy volunteers in medical research. The design of all 
studies should be publicly available. 
 
8. Physicians should abstain from engaging in research projects involving 
human subjects unless they are confident that the risks involved have been 
adequately assessed and can be satisfactorily managed. Physicians should 
cease any investigation if the risks are found to outweigh the potential benefits 
or if there is conclusive proof of positive and beneficial results. 
 
9. Medical research involving human subjects should only be conducted if the 
importance of the objective outweighs the inherent risks and burdens to the 
subject. This is especially important when the human subjects are healthy 
volunteers. 
 
10. Medical research is only justified if there is a reasonable likelihood that the 
populations in which the research is carried out stand to benefit from the 
results of the research. 
 
11. The subjects must be volunteers and informed participants in the research 
project. 
 
12. The right of research subjects to safeguard their integrity must always be 
respected. Every precaution should be taken to respect the privacy of the 
subject, the confidentiality of the patient's information and to minimize the 


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impact of the study on the subject's physical and mental integrity and on the 
personality of the subject. 
 
13. In any research on human beings, each potential subject must be adequately 
informed of the aims, methods, sources of funding, any possible conflicts of 
interest, institutional affiliations of the researcher, the anticipated benefits and 
potential risks of the study and the discomfort it may entail. The subject 
should be informed of the right to abstain from participation in the study or to 
withdraw consent to participate at any time without reprisal. After ensuring 
that the subject has understood the information, the physician should then 
obtain the subject's freely given informed consent, preferably in writing. If the 
consent cannot be obtained in writing, the non-written consent must be formally 
documented and witnessed. 
 
14. When obtaining informed consent for the research project the physician should 
be particularly cautious if the subject is in a dependent relationship with the 
physician or may consent under duress. In that case the informed consent 
should be obtained by a well- informed physician who is not engaged in the 
investigation and who is completely independent of this relationship. 
 
15. For a research subject who is legally incompetent, physically or mentally 
incapable of giving consent or is a legally incompetent minor, the 
investigator/treating physician must obtain informed consent from the legally 
authorized representative in accordance with applicable law. These groups 
should not be included in research unless the research is necessary to promote 
the health of the population represented and this research cannot instead 
be performed on legally competent persons. 
 
16. When a subject deemed legally incompetent, such as a minor child, is able to 
give 
assent 
to 
decisions 
about 
participation 
in 
research, 
the 
investigator/treating physician must obtain that assent in addition to the 
consent of the legally authorized representative. 
 
17. Research on individuals from whom it is not possible to obtain consent, 
including proxy or advance consent, should be done only if the 
physical/mental condition that prevents obtaining informed consent is a 
necessary characteristic of the research population. The specific reasons for 
involving research subjects with a condition that renders them unable to give 
informed consent should be stated in the experimental protocol for 
consideration and approval of the review committee. The protocol should 
state that consent to remain in the research should be obtained as soon as 
possible from the individual or a legally authorized surrogate. 
 
18. Both authors and publishers have ethical obligations. In publication of the 
results  of  research,  the  investigators/treating  physicians  are  obliged  to 


NIRAPARIB 
CONFIDENTIAL & PROPRIETARY 
PROTOCOL [TNE001] Amendment 31-Aug-2020 
 
67 
 
preserve the accuracy of the results. Negative as well as positive results 
should be published or otherwise publicly available. Sources of funding, 
institutional affiliations and any possible conflicts of interest should be 
declared in the publication. Reports of experimentation not in accordance with 
the principles laid down in this Declaration should not be accepted for 
publication. 
 
C. ADDITIONAL PRINCIPLES FOR MEDICAL RESEARCH COMBINED WITH 
MEDICAL CARE 
 
1. The physician may combine medical research with medical care, only to the 
extent that the research is justified by its potential prophylactic, diagnostic or 
therapeutic value. When medical research is combined with medical care, 
additional standards apply to protect the patients who are research subjects. 
 
2. . The benefits, risks, burdens and effectiveness of a new method should be 
tested against those of the best current prophylactic, diagnostic, and 
therapeutic methods. This does not exclude the use of placebo, or no 
treatment, in studies where no proven prophylactic, diagnostic or therapeutic 
method exists. 
 
3. At the conclusion of the study, every patient entered into the study should be 
assured of access to the best proven prophylactic, diagnostic and therapeutic 
methods identified by the study. 
 
4. The physician should fully inform the patient which aspects of the care are 
related to the research. The refusal of a patient to participate in a study must 
never interfere with the patient-physician relationship. 
 
5. In the treatment of a patient, where proven prophylactic, diagnostic and 
therapeutic methods do not exist or have been ineffective, the physician, with 
informed consent from the patient, must be free to use unproven or new 
prophylactic, diagnostic and therapeutic measures, if in the physician's 
judgment it offers hope of saving life, re-establishing health or alleviating 
suffering. Where possible, these measures should be made the object of 
research, designed to evaluate their safety and efficacy. In all cases, new 
information should be recorded and, where appropriate, published. The other 
relevant guidelines of this Declaration should be followed. 


NIRAPARIB 
CONFIDENTIAL & PROPRIETARY 
PROTOCOL [TNE001] Amendment 31-Aug-2020 
 
68 
APPENDIX 8 – SAFETY REPORTING INFORMATION 
 
Submission of Reports 
A central contact at the coordinating institution will forward all treatment emergent 
Serious Adverse Event (SAE) reports regardless of causality, to GSK within 24 hours 
of completion of the final report. The institution will forward both initial and follow-
up versions of each SAE report. The Institution will also provide reports for all 
pregnancies in the same manner. 
 
Format of SAE Reports 
All SAEs should be provided to GSK on a CIOMS I form; copies of the institution’s 
SAE form are not sufficient for reporting to GSK. Exact content should be entered 
directly from the institution’s SAE form into the CIOMS I format. Incomplete CIOMS 
I forms are acceptable. 
• For expected and/or unrelated events, it is not necessary to include a narrative. 
• For Suspected Unexpected Serious Adverse Reactions (SUSARs), please 
provide a comprehensive narrative for all events. 
 
GSK SAE and Pregnancy Reporting Information 
Drug Safety Alliance / Ashfield Pharmacovigilance 
Send all CIOMS/MedWatch to both: 
Email: OAX37649@gsk.com 
Fax: +44(0) 208754 7822 
 
 
SUSAR Distribution 
A central contact at the coordinating institution will forward any SUSARs that have 
occurred on other trials that involve the use of GSK’s Investigational Product for the 
duration of this study. 
 
 
 
 


NIRAPARIB 
CONFIDENTIAL & PROPRIETARY 
PROTOCOL [TNE001] Amendment 31-Aug-2020 
 
69 
APPENDIX 9 – Health Related Quality of Life Assessment 
HEALTH-RELATED QUALITY OF LIFE (HRQOL), LINEAR ANALOGUE 
SELF ASSESSMENT (LASA)  
Patient Name: _______________________________ 
Date: ______________________ 
Patient Number:  ______________________________ 
 
 
Directions: Please circle the number (0-10) best reflecting your response to the following 
that describes your feelings during the past week, including today. 
How would you describe: 
 
1. your overall Quality of Life? 
 
 
0 
1 2 
3 
4 
5 
6 
7 
8 
9 
10   
 
As bad as  
 
 
 
 
 
 
 
 
As good as 
 
it can be  
 
 
 
 
 
 
 
 
it can be 
 
2. your overall mental (intellectual) well being? 
 
 
0 
1 2 
3 
4 
5 
6 
7 
8 
9 
10   
 
As bad as  
 
 
 
 
 
 
 
 
As good as 
 
it can be  
 
 
 
 
 
 
 
 
it can be 
 
3. your overall physical well being? 
 
 
0 
1 2 
3 
4 
5 
6 
7 
8 
9 
10   
 
As bad as  
 
 
 
 
 
 
 
 
As good as 
 
it can be  
 
 
 
 
 
 
 
 
it can be 
 
4. your overall emotional well being? 
 
 
0 
1 2 
3 
4 
5 
6 
7 
8 
9 
10   
 
As bad as  
 
 
 
 
 
 
 
 
As good as 
 
it can be  
 
 
 
 
 
 
 
 
it can be 
 
5. your level of social activity? 
 
 
0 
1 2 
3 
4 
5 
6 
7 
8 
9 
10   
 
As bad as  
 
 
 
 
 
 
 
 
As good as 
 
it can be  
 
 
 
 
 
 
 
 
it can be 
 
6. your overall spiritual well being? 
 
 
0 
1 2 
3 
4 
5 
6 
7 
8 
9 
10   
 
As bad as  
 
 
 
 
 
 
 
 
As good as 
 
it can be 
it can be 
 
 
 
 
 
 


NIRAPARIB 
CONFIDENTIAL & PROPRIETARY 
PROTOCOL [TNE001] Amendment 31-Aug-2020 
 
70 
APPENDIX 10 – Therapy Related Symptoms Checklist 
THERAPY-RELATED SYMPTOMS CHECKLIST (TRSC) 
Name:                                                              Hospital #                   Date:            
  
PLEASE CHECK THE PROBLEMS YOU HAVE HAD IMMEDIATELY AFTER AND SINCE 
YOUR LAST TREATMENT.    PLEASE CIRCLE HOW SEVERE THE PROBLEM WAS 
ACCORDING TO THE FOLLOWING SCALE:  
  
0 = NONE          1 = MILD         2 = MODERATE         3 = SEVERE             4 = VERY SEVERE  
  
 
CHECK  
  
EXAMPLE  
Pain  
Degree of Severity (CIRCLE)  
0  
1  
2  
  
4  
  
Taste Change  
0  
1  
2  
3  
4  
  
Loss of appetite  
0  
1  
2  
3  
4  
  
Nausea  
0  
1  
2  
3  
4  
  
Vomiting  
0  
1  
2  
3  
4  
  
Weight loss  
0  
1  
2  
3  
4  
  
Sore mouth  
0  
1  
2  
3  
4  
  
Cough  
0  
1  
2  
3  
4  
  
Sore throat  
0  
1  
2  
3  
4  
  
Difficulty swallowing  
0  
1  
2  
3  
4  
  
Jaw pain  
0  
1  
2  
3  
4  
  
Shortness of breath  
0  
1  
2  
3  
4  
  
Numbness in fingers and/or toes  
0  
1  
2  
3  
4  
  
Feeling sluggish  
0  
1  
2  
3  
4  
  
Depression  
0  
1  
2  
3  
4  
  
Difficulty concentrating  
0  
1  
2  
3  
4  
  
Fever  
0  
1  
2  
3  
4  
  
Bruising  
0  
1  
2  
3  
4  
  
Bleeding  
0  
1  
2  
3  
4  
  
Hair loss  
0  
1  
2  
3  
4  
  
Skin changes  
0  
1  
2  
3  
4  
  
Soreness   in   vein   where   chemotherapy  
was given  
0  
1  
2  
3  
4  
  
Difficulty sleeping  
0  
1  
2  
3  
4  
  
Pain  
0  
1  
2  
3  
4  
  
Decreased interest in sexual activity  
0  
1  
2  
3  
4  
  
Constipation  
0  
1  
2  
3  
4  
 
Other problems (please list below)  
  
  
  
  
  
  
0  
1  
2  
3  
4  
  
0  
1  
2  
3  
4  
  
0  
1  
2  
3  
4  
  
0  
1  
2  
3  
4  
Phoebe D. Williams, PhD ©Copyright 1995 University of Kansas Medical Center 

ICF_001.pdf: 
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PATIENT INFORMATION AND CONSENT DOCUMENT 
 
 
TITLE:   
A Phase 1 Evaluation of the Safety and Tolerability of Niraparib in 
Combination with Everolimus in Advanced Gynecologic 
Malignancies and Breast Cancer 
 
PROTOCOL NO.: 
TNE001 
 
WIRB® Protocol #20171364 
 
SPONSOR: 
Avera Cancer Institute 
 
INVESTIGATOR: 
Casey Williams, PharmD, BCOP 
 
Avera Cancer Institute 
1000 East 23rd Street 
Sioux Falls, SD, 57105 
 
PHONE NUMBER: 
605-322-3211 (24-hours) 
 
 
 
 
 
Summary 
 
You are being invited to participate in a medical research study. This document gives you 
important information about the study.  It describes the purpose of the study, and the risks and 
possible benefits of participating in the study. You are being invited to volunteer since you may 
meet the requirements for enrollment into this study. Your participation is voluntary which 
means you can choose whether or not you want to participate. If you choose not to participate, 
there will be no loss of benefits to which you are otherwise entitled.  
 
Please take time to review this information carefully.  After you have finished, you should talk to 
the research team about the study and ask them any questions you have.  You may also wish to 
talk with family, friends or family doctor about your participation in this study.  If you decide to 
participate, you will be asked to sign this document.  You will be given a signed copy of the 
consent document to take home and keep for your records.  Before you sign this document, be 
sure you understand what the study is about, including the risks and possible benefits to you. 
 
Things to know before deciding to take part in a research study: 
• The main goal of a research study is to learn things to help patients in the future. 
• The main goal of regular medical care is to help each patient. 
• The decision to join or not join the research study will not cause you penalty or loss of 
benefits to which you are otherwise entitled. 
• Parts of this study may involve standard medical care. Standard care is the treatment 
normally given for a certain condition or illness. 
• After reading the consent and having a discussion with the research staff, you should 
know which parts of the study are experimental and which are standard medical care. 


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• Your medical insurance may be billed for any standard medical care you receive during 
the research study. If your insurance company is billed then it may have access to the 
research records. Insurance companies may not pay for treatment that is part of a research 
study. Taking part in a research study could affect your current or future insurance 
coverage. 
 
A description of this clinical trial will be available on http://www.ClinicalTrials.gov, as required 
by U.S. Law. This Web site will not include information that can identify you. At most, the Web 
site will include a summary of the results. You can search this Web site at any time. 
 
What is the purpose of this research study? 
 
You are invited to participate in this research study because you have been diagnosed with an 
advanced gynecologic malignancies or breast cancer.  Your cancer has either grown back 
(relapsed) or has never gone away after standard treatment.  Standard treatment may have 
included chemotherapy, surgery, radiation therapy, and/or targeted therapy. 
 
The purposes of this research study are: 
• To determine if your tumor gets smaller after treatment with niraparib and everolimus 
• To determine if specific molecular changes in the genetics of your tumor make you more 
likely to respond to the combination of niraparib and everolimus 
 
Niraparib is a study drug that has been approved by the FDA for certain diagnoses.  Niraparib 
belongs to a category of drugs called PARP inhibitors, which have the potential to selectively kill 
cancer cells by affecting the DNA repair mechanisms.  Niraparib has been developed to address 
DNA repair defects, and has shown to be effective in previous studies. 
 
Everolimus is an FDA approved anti-cancer therapy drug that is used to treat multiple types of 
cancer including breast cancer.  Everolimus works by blocking signaling pathways that are 
important in the growth of cancer cells.  Everolimus is currently not approved in gynecologic 
malignancies.  Niraparib and everolimus have not been previously studied in combination and 
their combination is investigational. 
 
Giving niraparib and everolimus together may be effective in treating some cancers. The dose-
finding portion of this study has been completed and our investigators have found the highest 
tolerated dose combination. 
 
How long will I be in the study? 
 
You may stay on study as long as you are not having bad side effects and as long as your tumor 
is not getting worse.  After you stop treatment, you will continue to be followed for up to five 
years. 
 
How many other people will be in the study? 
 
It is expected that up to 24 people will take part in this study at the Avera Cancer Institute. 
 


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What am I being asked to do? 
 
Before any study procedures can be performed, you must sign this informed consent document.  
You will need to have the following exams, tests or procedures to find out if you are able to be 
enrolled into this study.  Some of these exams, tests, or procedures are part of regular cancer care 
and may be done even if you do not join the study.  These tests will also be done at various times 
throughout the study and at the end of the study. 
 
Screening Period 
The following must take place within 28 days before entering the study: 
• Medical history– a discussion of your past and present health issues, including a 
discussion of your cancer history and treatments, and any medications you have taken in 
the past 30 days and are taking currently 
• Demographic information – collecting information regarding your date of birth, race, 
gender, and ethnicity 
• Vital Signs – this includes your temperature, blood pressure, pulse, and oxygen saturation 
• Blood tests – this will include routine laboratory tests in addition to a lipid panel, and a 
test that will examine your chromosomes to determine your risk for developing a blood 
disorder called myelodysplastic syndrome 
• Serum (blood) pregnancy test (if applicable) – this will be done for females that are of 
childbearing potential, and will need to be performed less than 72 hours prior to the first 
dose of study drug. 
• Tumor assessment – either a Computerized Tomography (CT) scan or Magnetic 
Resonance Imaging (MRI).  If you have already had a tumor assessment within 28 days 
then you will not need to repeat this.   
 
During the Treatment Phase 
If the exams, tests and procedures show that you can be in the study, you will return to your 
study doctor’s office for the following exams, tests, and procedures at the following time-points 
during the time you are receiving treatment: 
 
Day 1 of each cycle (each cycle is 28 days): 
• Physical exam including vital signs 
• ECOG status – an evaluation of how well you perform normal daily activities 
• Review any medications you are taking 
• Review medication diary – you will be asked to keep a medication diary for the niraparib 
and everolimus and review this with the study staff at each visit  
• Monitoring of any side effects – each time you speak with the study staff you should let 
them know about any side effects you are having and/or health issues you have had since 
the last visit 
• Routine laboratory tests 
• Completion of questionnaires about symptoms you may be experiencing as well as your 
quality of life 
 
Days 8, 15, and 22 of cycle 1 only (each cycle is 28 days): 
• Physical exam including vital signs 


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• Monitoring of any side effects – each time you speak with the study staff you should let 
them know about any side effects you are having and/or health issues you have had since 
the last visit 
• Routine laboratory tests 
 
Treatment Plan 
Investigators have found the highest tolerated dose of everolimus and niraparib that can be given 
together without bad side effects.   
 
You will take everolimus 5mg by mouth on Mondays, Wednesdays, and Fridays.  You will take 
niraparib 100mg by mouth every day. 
 
Study Day 
1 
2 
3 
4 
5 
6-28 
Everolimus 5mg 
X 
 
X 
 
X 
Continue 
on MWF 
Niraparib 100mg 
X 
X 
X 
X 
X 
X 
 
The treatment will be given in cycles where each cycle lasts 28 days. 
 
End of Treatment 
After you stop treatment with everolimus and niraparib, you will have the following tests 
performed: 
• Blood tests – this will include a lipid panel and a whole blood sample that may be used to 
determine risk for developing myelodysplastic syndrome. 
• Monitoring of any adverse events that you are experiencing 
• Completion of questionnaires about symptoms you may be experiencing as well as your 
quality of life 
 
Post-Study Assessments 
The following assessments will also take place after you stop the study: 
• Monitoring of any adverse events that you are experiencing for 30 days following the last 
dose of drug 
• Survival assessment will occur every 8 weeks for at least 5 years.  This can usually occur 
by gathering information from your medical chart but it may be necessary for a person 
involved in this research study to contact you. 
 
What are the possible risks or discomforts?  
 
As with all research studies, the study treatment and study procedures may involve unknown 
risks. Any medication can have temporary or permanent side effects that may or may not be 
expected.  
 
A phase I study looks at how common and serious side effects can be for each patient.  In a 
phase I study, some patients could have very serious side effects and could die as a result of 
these side effects. 
 
Everyone taking part in this study will be watched very carefully for any side effects, however 
providers don’t know all the side effects that may happen.  Side effects may be mild or very 


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serious.  Side effects may go away soon after you stop taking everolimus and niraparib, but it is 
always possible that some side effects will be long lasting or may never go away.  Patients are 
watched carefully and treatment will be stopped if bad side effects develop.  Known potential 
side effects for each drug are listed below: 
 
Everolimus 
 
The most common side effects (greater than 10% occurrence) noted in previous studies: 
• Peripheral edema (swelling in legs, feet, hands) 
• High blood pressure 
• Fatigue 
• Headache 
• Rash 
• Increased cholesterol and triglycerides 
• Increased blood sugar 
• Diarrhea 
• Mouth sores 
• Taste changes and/or loss of appetite 
• Low hemoglobin 
• Low platelet count 
• Low white blood cell count 
• Liver function test abnormalities that could indicate liver damage 
• Cough 
• Pneumonitis (inflammation of the lining of the lungs) 
• Increased risk of many types of infections 
 
1-10% occurrence: 
• Poor wound healing 
• Chest pain 
• Rapid heart rate 
• Heart failure 
• Blood clots 
• Numbness and/or tingling in fingers and/or toes 
• Hair loss 
• Muscle spasm  
• Renal function test abnormalities that could indicate renal damage  
 
Less than 1% occurrence: 
• Increased risk of opportunistic infections  
• Risk of angioedema with concomitant use of ACE inhibitors 
• Kidney failure that could lead to death 
• Hepatitis B reactivation  
 


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Niraparib 
 
Niraparib has been studied in more than 1902 patients in TESARO clinical trials. Niraparib 
capsule is marketed as ZEJULA® and is approved to treat adult patients with recurrent epithelial 
ovarian, fallopian tube, or primary peritoneal cancer in the United States and in Europe. 
Niraparib is currently being studied as a single medication and as a combination therapy within a 
variety of cancer clinical studies. 
 
Niraparib single drug therapy has resulted in the following side effects 
 
Very Common (greater than 10% occurrence): 
 
• Low platelet count (helps blood to clot) 
• Low hemoglobin (red blood cells) that causes anemia 
• Low white blood cell count (helps fight infection) 
• Low neutrophil count (another type of white blood cell that helps fight infection) 
• High blood pressure  
• Heart palpitations 
• Painful and frequent urination (urinary tract infection) 
• Shortness of breath 
• Runny or stuffy nose 
• Cough  
• Headache  
• Dizziness  
• Weakness 
• Fatigue 
• Insomnia 
• Joint pain  
• Back pain 
• Stomach pain (abdominal pain) 
• Indigestion 
• Nausea 
• Vomiting 
• Diarrhea 
• Constipation 
• Decreased appetite 
 
Common (less than or equal to 10% occurrence): 
• Infection from low white blood cell counts 
• Bronchitis (inflammation of the lining of the bronchial tubes in your lungs) 
• Fast heart beat (tachycardia) 
• Swelling of lower legs and feet (peripheral edema) 
• Muscle pain 
• Rash 
• Weight loss 
• Depression 


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• Feelings of worry, nervousness or unease (anxiety)   
• Inflammation of the eye (conjunctivitis) 
• Nose bleeds 
• Sore, red mouth (stomatitis)  
• Swelling or irritation of the lining of the mouth, throat, esophagus, stomach or intestines 
(Mucosal inflammation) 
• Altered sense of taste 
• Dry mouth 
• Increased sensitivity of the skin to sunlight  
• Decrease in potassium in the blood (hypokalaemia) 
• Kidney function test abnormalities (blood creatinine increase), that could indicate kidney 
damage  
• Liver function test abnormalities that could indicate liver damage (aspartate 
aminotransferase [AST] increased, alanine aminotransferase [ALT] increased, gamma-
glutamyl transferase [GGT] increased) 
• Other abnormal labs (alkaline phosphatase [ALP] increased) 
 
Uncommon Occurrence (less than or equal to 1% occurrence) 
• Fever with low white blood cell count (febrile neutropenia) 
• Decrease in number of all types of blood cells (pancytopenia) 
 
Rare Occurrence (less than or equal to 0.1% occurrence): 
• Severe life-threatening infection due to low white cell counts (associated with low blood 
pressure and possible organ failure (for example, heart, kidney and/or liver) (neutropenic 
sepsis)  
• Severe increase in blood pressure (hypertensive crisis) 
• A brain condition with symptoms including seizures, headache, confusion, and changes in 
vision (posterior reversible encephalopathy syndrome [PRES]) 
 
In addition to the above, the side effects below were reported by patients who were 
prescribed niraparib by their doctors:  
•  Allergic reaction (hypersensitivity, including anaphylaxis)  
o Life-threatening allergic reaction (such as difficulty breathing, rash, localised 
swelling, such as tongue, throat or lips) (anaphylaxis) 
• Confusion (confusional state) 
• Disorientation 
• Seeing or hearing things that are not really there (hallucination)  
• Impaired concentration, understanding, memory and thinking (cognitive impairment) 
• Inflammation of the lungs which can cause shortness of breath and difficulty breathing (non-
infectious pneumonitis) 
 
Side Effects Requiring Immediate Medical Attention: 
The side effects listed below require IMMEDIATE MEDICAL ATTENTION OR ADVICE.  
Call the study doctor right away if you have any of these side effects: 
• Allergic reactions can be life-threatening.  Symptoms may include difficulty breathing, 
shortness of breath, low blood pressure (feeling lightheaded, dizziness), tingling around the 
mouth, rash. 


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• Low platelet counts may increase your risk of bleeding and bruising.  Bleeding may require 
urgent medical attention, including a transfusion (receiving blood or blood products by 
vein). 
• Low red blood cell counts may make you feel tired or short of breath and symptoms may 
require a blood transfusion. 
• Low neutrophil counts may be associated with infection, sometimes severe and life-
threatening. 
o Symptoms of severe life-threatening infection may include: 
 Fever, feeling of low blood pressure (lightheadedness, dizziness), 
decreased urination, rapid pulse, rapid breathing or shortness of breath 
• High blood pressure (hypertension) including severe increase in blood pressure 
(hypertensive crisis) has been reported with the use of niraparib. If you have pre-existing 
hypertension, the physician will determine if your blood pressure is adequately controlled 
before starting niraparib treatment.  
o Symptoms of a severe increase in blood pressure may include: 
 Blurry vision, headache, nausea, vomiting, confusion, passing out, 
seizures, weakness or numbness on one side of body or in one arm or leg 
and/or difficulty talking (symptoms of a stroke), trouble breathing, chest 
pain, pain in the upper or lower back, urine that is brown or bloody 
• A rare neurological side effect named Posterior Reversible Encephalopathy Syndrome 
(PRES) has been associated with treatment. If you have headache, vision changes, 
confusion or seizure with or without high blood pressure, please contact your doctor. 
 
A very rare (less than 1%) but serious side effect that may occur with niraparib is the 
development of a blood disorder called myelodysplastic syndrome (MDS), which typically 
progresses to a blood cancer called acute myeloid leukemia (AML).  It is not clear from previous 
studies whether niraparib increases the risk for developing MDS/AML or whether other risk 
factors are the main cause.  As a result of this potential risk, additional safety precautions and 
monitoring have been added to this study. 
 
Secondary Primary Malignancy: 
PARP inhibitors may also cause a new primary cancer (that is, a cancer other than the one for 
which you have been treated). In 2 studies comparing niraparib to placebo, the likelihood of 
getting a new primary cancer in patients who took niraparib was similar to those in patients who 
took placebo. 
 
Reproductive risks: 
You cannot participate in this study, if you are pregnant, planning to become pregnant, or are 
breastfeeding. Due to the effect of this drug, there could be serious harm to unborn children (or 
children who are breast-feeding) and it could also jeopardize the health of the mother.  In 
addition, it is possible that harmful side effects that are not yet known could occur to both the 
mother and unborn or breast-feeding child.  The risks to an unborn child or a nursing child from 
the study drug are not known. 
 
Females: 
Due to the unknown effects of this study’s drug(s) on an unborn child, you understand that it is 
very important that you do not become pregnant during this study.  Avoiding sexual activity 
(total abstinence) is the only certain method to prevent pregnancy.  However, if you do choose to 


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be sexually active, you must agree to use acceptable method(s) of pregnancy prevention while in 
this research study and for at least 30 days after receiving study drug.  Please discuss with your 
doctor the most appropriate method(s) of preventing pregnancy for you that also respects your 
cultural and religious values and traditions.  If you do become pregnant, notify the study doctor 
and/or study staff immediately.  You will be asked to withdraw from the study. The Study 
Doctor is required to follow up and document the course and the outcome of all pregnancies, 
even if you withdraw from the study or if the study has finished. 
 
You must not breast-feed an infant (or store breastmilk for use) during the study and for 30 days 
after receiving final dose of study drug. 
 
Males:  
Due to the unknown effects of this study's drugs on a human unborn child, you understand the 
risk of birth defects if your partner becomes pregnant during this study.  Avoiding sexual activity 
(total abstinence) is the only certain method to prevent pregnancy.  However, if you choose to be 
sexually active, you must agree to use acceptable method(s) of pregnancy prevention while in 
this research study and for at least 90 days after receiving study drug.  Please discuss with your 
doctor the most appropriate method(s) of preventing pregnancy for you that also respects your 
cultural and religious values and traditions.  Inform your study doctor if you think for any reason 
that your partner might be pregnant. 
 
If you agree to participate in this study, you are expected to inform your female sexual partner(s) 
that you are participating in a clinical research study of an investigational drug, and that the 
effects of the drug on sperm, an unborn baby and on a pregnant woman are unknown.  If your 
female partner becomes pregnant while you are participating in this study or within 90 days after 
your last dose of Study Drug, tell your Study Doctor or study nurse right away as the Study 
Doctor is required to follow up and document the course and the outcome of all pregnancies. The 
Study Doctor may seek the pregnant woman’s permission to review her medical records and the 
infant’s medical records up to delivery, if applicable. The Study Doctor will share the 
information about your pregnant partner and the baby with the Sponsor to help understand the 
effects, if any, that the Study Drug may have on the pregnancy and maybe the child. 
 
You must not donate sperm for 90 days after your last dose of Study Drug. 
 
Fertility Preservation: 
If you may wish to become pregnant or father a child in the future, please discuss fertility 
preservation options with your doctor before you begin participating in this study. 
 
What are the possible benefits of the study? 
 
There may or may not be direct medical benefit to you.  The information learned from this study 
may or not benefit patients in the future. 
 
What if new information becomes available about the study? 
 
During the course of this study, we may find more information that could be important to you.  
This includes information that, once learned, might cause you to change your mind about being 
in the study.  We will notify you as soon as possible if such information becomes available. 


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What other choices do I have if I do not participate? 
 
Instead of being in this study you may have the following options: 
• Treatment with chemotherapy medicines 
• If you have breast cancer, depending on your previous treatment, you could receive 
everolimus plus exemestane without being in the study. 
• If you have advanced gynecologic malignancies cancer, depending on your disease 
status, you may be able to receive niraparib or olaparib without being in the study. 
• Treatment with other experimental agents that may be available 
• No further therapy, with a focus on care that will make you more comfortable 
 
Your provider will discuss alternative options with you. 
 
Will I be paid for being in this study? 
 
You will not be paid for being in this research study. 
 
Will I have to pay for anything? 
 
You and/or your health insurance company will be responsible for the cost of treatments and 
procedures that would be done whether or not you took part in this study.  This includes the drug 
everolimus.  It is important to understand that some insurance companies do not cover some 
costs (for example approved drugs used in a way different from the package instructions).  If 
your insurance company does not cover these treatments or procedures, you will be required to 
pay for them. 
 
The study drug, Niraparib, will be provided by Tesaro, the company that makes this drug.  
Tesaro is now owned by GlaxoSmithKline, LLC (GSK).  They will provide the Niraparib at no 
cost to you. 
 
Ask the study staff if you have any questions about bills, fees or other costs related to this study. 
 
What happens if I am injured or hurt during the study? 
 
If you have a medical emergency during the study you should go to the nearest emergency room. 
You may contact the study doctor or Emergency contact listed on page one of this form. You 
may also contact your own doctor, or seek treatment outside of the Avera.  Be sure to tell the 
doctor or his/her staff that you are in a research study being conducted at the Avera Cancer 
Institute.  Ask them to call the telephone numbers on the first page of this consent form for 
further instructions or information about your care. 
 
In the event of any physical injury resulting from research procedures, medical treatment will be 
provided without cost to you, but financial compensation is not otherwise available from the 
Avera Cancer Institute.  If you have an illness or injury during this research trial that is not 
directly related to your participation in this study, you and/or your insurance will be responsible 
for the cost of the medical care of that illness or injury. 
 
When is the Study over?  Can I leave the Study before it ends? 


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This study is expected to end after all participants have completed all visits, and all information 
has been collected.  This study may also be stopped at any time by your physician, the study 
Sponsor, or the Food and Drug Administration (FDA) without your consent because: 
• The study doctor feels it is necessary for your health or safety.  Such an action would not 
require your consent, but you will be informed if such a decision is made and the reason 
for this decision. 
• You have not followed study instructions. 
• The Sponsor, the study doctor, or the Food and Drug Administration (FDA) has decided 
to stop the study. 
 
You may choose to participate or not participate in this research study. You are not waiving any 
legal rights by agreeing to participate or participating in this study. If you decide to take part in 
this research study, you may remove yourself from the study at any time.  No matter what 
decision you make about participating or stopping your participation, there will be no penalty to 
you and you will not lose any of your regular benefits to which you are otherwise entitled.  
Withdrawal will not interfere with your future care. If you no longer wish to participate, you 
must let us know in writing by sending a letter to:  
 
Dr. Casey Williams 
Avera Cancer Institute 
1000 East 23rd Street 
Sioux Falls, SD  57105 
 
Confidentiality of Study Records and Medical Records. 
 
Information collected for this study is confidential.  However, the sponsor company, 
Tesaro/GSK, and the Food and Drug Administration (FDA) of the U.S. Government will receive 
copies of the study records.  Employees of Tesaro/GSK, the FDA, and the Institutional Review 
Board may see parts of your medical records related to this study.  Data collected and entered 
into the Case Report Forms are the property of Tesaro/GSK.  In the event of any publication 
regarding this study, your identity will not be disclosed. 
 
Who can see or use my information?  How will my personal information be protected? 
 
Signing this form gives the researchers your permission to obtain, use, and share information 
about you for this study, and is required in order for you to take part in the study.  Information 
about you may be obtained from any hospital, doctor, and other health care provider involved in 
your care. 
 
Information about you may include information about your health and your medical care before, 
during, and after the study, even if that information wasn't collected as part of this research 
study.  For example: 
• Hospital/doctor's office records, including test results (X-rays, blood tests, urine tests, etc.) 
• Mental health care records (except psychotherapy notes not kept with your medical records) 
• Alcohol/substance abuse treatment records 
• All records relating to your cancer, the treatment you have received, and your response to the 
treatment 


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• Billing information 
 
There are many reasons why information about you may be used or seen by the researchers or 
others during this study.  Examples include: 
• The researchers may need the information to make sure you can take part in the study. 
• The researchers may need the information to check your test results or look for side effects. 
• Tesaro/GSK, the Food and Drug Administration [FDA], and other government officials may 
need the information to make sure that the study is done properly. 
• Organizations that are funding the study may need the information to make sure that the 
study is done properly. 
• Safety monitors or committees may need the information to make sure that the study is safe.   
• Insurance companies or other organizations may need the information in order to pay your 
medical bills or other costs of your participation in the study. 
• The researchers may need to use the information to create a databank of information about 
your condition or its treatment. 
 
Your health information and any research data derived from it will be stored for a minimum of 
ten years, at which time the need to retain it will be reviewed. 
 
The results of this study could be published in an article, but would not include any information 
that would let others know who you are.  
 
What happens to information about me after the study is over or if I cancel my permission? 
 
As a rule, the researchers will not continue to use or disclose information about you, but will 
keep it secure until it is destroyed.  Sometimes, it may be necessary for information about you to 
continue to be used or disclosed, even after you have canceled your permission or the study is 
over.  Examples of reasons for this include: 
• To avoid losing study results that have already included your information  
• To provide limited information for research, education, or other activities  (This 
information would not include your name, social security number, or anything else that 
could let others know who you are.)  
• To help regulatory and government officials make sure that the study was conducted 
properly 
 
When does my permission expire?  
 
Your permission will not expire unless you cancel it. You may cancel your permission at any 
time by writing to the study staff listed on the first page of this document. 
 


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Who can I call about my rights as a research subject? 
 
If you have questions regarding your rights as a research subject, you may contact:  
 
 
Western Institutional Review Board® (WIRB®) 
 
1019 39th Avenue SE Suite 120 
 
Puyallup, Washington  98374-2115 
 
Telephone:  1-800-562-4789 or 360-252-2500 
 
E-mail: Help@wirb.com 
 
(An Institutional Review Board [IRB] is a committee established to review and approve research 
involving human subjects.  The purpose of the IRB is to ensure that all human subject research 
be conducted in accordance with all federal, institutional, and ethical guidelines.)  
 
• You may also call this number to discuss or report any problems, questions, complaints, 
or concerns you have about this research study. 
• WIRB will not be able to answer some study-specific questions, such as questions about 
appointment times.  You may also call this number if you cannot reach research staff, or 
you wish to talk with someone who is independent of the research team. 
 


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Consent 
 
When you sign this document, you are agreeing to take part in this research study. This means 
that you have read the consent form, your questions have been answered, and you have decided 
to volunteer.  If you have additional questions, concerns or complaints about taking part in this 
study or research-related injury, you may contact Dr. Casey Williams at 605-322-3211 (24-
hours). 
 
You understand taking part in this research study is voluntary.  You may quit the study at any 
time without harming future medical care or losing any benefits to which you might otherwise be 
entitled. 
 
I have read and understand the above information.  I agree to take part in this study.  I will be 
given a copy of this document for my own records. 
 
 
 
 
 
 
 
 
Name of Subject (Please Print) 
Signature of Subject 
Date 
 
 
 
 
 
 
 
 
Name of Person Obtaining 
Signature of Person 
Date 
Consent (Please Print) 
Obtaining Consent