Clinical trial NCT05297864
Conditions: Recurrent Glioblastoma Recurrent Astrocytoma Recurrent Oligodendroglioma Recurrent Glioma
Keywords: high grade gliomas
Sponsor: University of Oklahoma
Start date: 2022-06-09; Completion date: 2024-02-06
Enrollment: 15 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
The purpose of this study is to determine what effects (good and bad) niraparib has on patients with recurrent brain cancer.

Detailed description:
Patients will have tests and exams to see if they are eligible for the clinical trial. If found eligible, the patient will receive treatment with niraparib in the form of capsules taken every day for the first 28 days. If this dose is tolerated well, the patients will continue to take the capsules and more patients will be enrolled on the study.

Patients will continue treatment with niraparib while on the study unless there is evidence of tumor growth or they experience unacceptable side effects.

Patients will be monitored during treatment with tests and exams and after treatment completion for up to four years from the time they enrolled on the study.

Arms: arm 1: Patients will be treated with individualized starting dose of Niraparib.
Interventions: intervention 1: Niraparib
Intervention descriptions: intervention 1: The starting dose will be 300 mg niraparib (or modified according patient weight and platelet count), taken orally once a day for each cycle of 28 days.

Protocol documents:
Prot_000.pdf: 
Version 5.0 (30-Aug-2022) 
OU-SCC-PI-4G 
1 
 
CLINICAL STUDY PROTOCOL 
 
Full Study Title:  
Phase II Trial of Niraparib in Patients with Recurrent Glioma  
 
Brief Title:  
PARP Inhibition for Gliomas (PI-4G or 4g) 
 
Sponsor ID Number:            OU-SCC-PI-4G 
 
Sponsor:  
The University of Oklahoma Health Sciences Center     
Stephenson Cancer Center 
 
800 NE 10th Street 
 
Oklahoma City, OK 73104 
 
Test Product:  
 
Niraparib 
 
Principal Investigator:  
James Battiste, MD, PhD 
Neuro-Oncology  
Stephenson Cancer Center 
800 NE 10th Street, Oklahoma City, OK 73104 
 
 
 
     
E-mail: James-Battiste@ouhsc.edu  
 
Co-Investigators:  
 
Maya Hrachova, MD 
Neuro-Oncology, Stephenson Cancer Center 
800 NE 10th Street, Oklahoma City, OK 73104 
 
 
 
     
                                                
 
Michael Pearlman, MD, PhD 
Blue Sky Neurology 
499 E Hampden Ave Ste 360, Englewood, CO 80113 
 
Statistician:   
 
Daniel Zhao, PhD 
Biostatistics & Epidemiology,  
 
 
 
University of Oklahoma Health Sciences Center 
 
 
 
801 NE 13th Street, Oklahoma City, OK 73104 
 
Funding Collaborator:  
GSK Inc. 
 
 
NCT Number: 
NCT05297864 
 
Protocol Writer:  
Yuejin Wen, PhD, MD 
 
 
 
 
 
 
 
 


Version 5.0 (30-Aug-2022) 
OU-SCC-PI-4G 
2 
 
TABLE OF CONTENTS 
 
 
BACKGROUND INFORMATION .......................................................................................................... 4 
 
Study Hypothesis .......................................................................................................................... 4 
 
Disease Background ...................................................................................................................... 4 
 
PARP Inhibitor on Brain Tumor ..................................................................................................... 4 
 
Summary of Investigational Drug.................................................................................................. 6 
 
Rationale for this study ................................................................................................................. 8 
 
STUDY OBJECTIVES AND ENDPOINTS................................................................................................ 8 
2.1 
Study Objectives ........................................................................................................................... 8 
2.2 
Study Endpoints ............................................................................................................................ 9 
 
INCLUSION / EXCLUSION CRITERIA ................................................................................................... 9 
3.1 
Inclusion Criteria ........................................................................................................................... 9 
3.2 
Exclusion Criteria ......................................................................................................................... 11 
 
SUBJECT REGISTRATION AND ENROLLMENT .................................................................................. 12 
4.1 
Required protocol specific regulatory documents ..................................................................... 12 
4.2 
Patients Registration and Enrollment ......................................................................................... 12 
 
SCHEMA AND TREATMENT PLAN .................................................................................................... 13 
5.1 
Schema ........................................................................................................................................ 13 
5.2 
Study Treatment ......................................................................................................................... 13 
5.3 
Treatment Plan ........................................................................................................................... 14 
5.4 
Dose Modification ....................................................................................................................... 14 
5.5 
Precaution for Concomitant Medications ................................................................................... 17 
5.6 
Breast Feeding ............................................................................................................................ 19 
5.7 
Blood Donation ........................................................................................................................... 19 
5.8 
Supportive Care........................................................................................................................... 19 
5.9 
Duration of Therapy .................................................................................................................... 19 
5.10 
Duration of Follow-up ................................................................................................................. 19 
 
STUDY DESIGN AND PARAMETERS ................................................................................................. 19 
6.1 
Study Design................................................................................................................................ 19 
6.2 
Study Parameters ........................................................................................................................ 20 
 
STUDY MEDICATION ....................................................................................................................... 23 
7.1 
Niraparib ..................................................................................................................................... 23 


Version 5.0 (30-Aug-2022) 
OU-SCC-PI-4G 
3 
 
 
EVALUATION CRITERIA .................................................................................................................... 24 
8.1 
Parameters of Outcome – RANO Criteria or Macdonald Criteria ............................................... 24 
8.2 
Subjective Parameters: ............................................................................................................... 27 
 
Safety Monitoring and Reporting Procedures ................................................................................ 27 
9.1 
Adverse Event Monitoring and Management ............................................................................ 28 
9.2 
MedWatch 3500A Reporting Guidelines .................................................................................... 34 
9.3 
Study Monitoring ........................................................................................................................ 35 
9.4 
Data Disclosure and Patient Confidentiality ............................................................................... 35 
 
STATISTICAL ANALYSIS PLAN ........................................................................................................... 36 
10.1 
Analysis Populations ................................................................................................................... 36 
10.2 
Data Analysis ............................................................................................................................... 36 
10.3 
Accrual and Study Duration ........................................................................................................ 38 
 
DATA MANAGEMENT PLAN ............................................................................................................ 39 
11.1 
Data Quality Assurance ............................................................................................................... 39 
11.2 
Electronic Case Report Forms ..................................................................................................... 39 
11.3 
Data and Safety Monitoring Committee ..................................................................................... 39 
11.4 
DSMC Auditing ............................................................................................................................ 39 
11.5 
Record Retention ........................................................................................................................ 39 
 
PUBLICATION PLAN ......................................................................................................................... 40 
 
ETHICAL AND REGULATORY CONSIDERATIONS .............................................................................. 41 
13.1 
Ethical Conduct of the Study ....................................................................................................... 41 
13.2 
Informed Consent ....................................................................................................................... 41 
13.3 
Institutional Review Board or Ethics Committee ........................................................................ 41 
13.4 
Protocol Violations/Deviations ................................................................................................... 41 
 
REFERENCES .................................................................................................................................... 42 
 
APPENDIX ........................................................................................................................................ 44 
 
 
 


Version 5.0 (30-Aug-2022) 
OU-SCC-PI-4G 
4 
 
 BACKGROUND INFORMATION 
 
 Study Hypothesis 
Poly (ADP-ribose) polymerase (PARP) is a family of proteins involved in many cellular 
processes such as DNA repair and programmed cell death [1]. Cancer cells may use PARP to 
repair DNA damage and become resistant to treatment. Therefore PARP inhibitors have been 
developed as novel drugs that may be used to enhance the antitumor activity of some agents, 
like temozolomide which can induce DNA damage and is the drug of choice for glioblastoma 
multiforme (GBM) [2]. Moreover, PARP inhibitors demonstrated cytotoxic effects in 
monotherapy and can selectively kill a subset of cancer cells with deficiencies in DNA repair 
pathways [3, 4]. Niraparib is an oral potent PARP inhibitor and has shown to significantly 
improve progression-free survival for patients with ovarian cancer with manageable toxicities [5]. 
Studies in pre-clinical setting suggested niraparib could cross the blood brain barrier and 
inhibited intracranial tumor growth in animal models [6, 7]. It will be worthwhile to investigate the 
clinical safety and anti-cancer benefit of niraparib on patients with GBM in a prospective study.   
 
 Disease Background 
GBM is the most common, highest grade, and most malignant primary brain tumor [8]. With 
introduction of the Stupp protocol in 2005, patients diagnosed with a GBM have a median 
survival of 14.5 months [9, 10]. The annual incidence of primary brain malignant neoplasms in 
the U.S. is 4.3 per 100,000 with a total of 23,770 people diagnosed per a year [11]. This number 
is expected to grow as the nation’s population ages.  The standard treatment with radiotherapy 
and chemotherapy (temozolomide) provide patients with, approximately 2.5 months benefit. The 
unfortunate reality in the current treatment of GBM is that it inevitably recurs after initial 
treatment with radiation and temozolomide, and it has a high mortality despite second line 
treatments such as bevacizumab and carmustine [12]. By default that necessitates that at least 
some of the tumor cells are resistant to these therapies. Novel treatments are needed to focus 
on the mechanisms of resistance in glioblastoma. 
 
 PARP Inhibitor on Brain Tumor 
PARPs play critical roles in DNA repair which can promote cancer cells resistant to DNA 
damaging therapy. Microarray analysis of PARP-1 gene expression in more than 8000 samples 
revealed that PARP-1 is more highly expressed in several types of tumors compared with the 
equivalent normal tissue [13]. By using immunohistochemical staining, positive nuclear PARP-1 
staining was found in all GBM samples collected from patients (n=27), but not in normal 
neurons from controls (n=4) and GBM patients (n=27) [14]. In non-clinical studies, combining 
PARP inhibitor (veliparib) with radiation and/or temozolomide yielded enhanced cell killing in 
GBM cell lines [15]. In addition, PARP inhibition by olaparib could overcome apoptotic 
resistance and sensitizes GBM cell lines for death receptor-mediated apoptosis [16]. 
 
Niraparib is a novel drug that selectively inhibits PARP-1 and PARP-2 and produced anti-cancer 
effect in preclinical studies. Comparing to olaparib and veliparib, niraparib was the most potent 
drug in trapping PARP and revealed the highest cytotoxicity to BRCA-deficient cancer cells [4]. 
Furthermore, niraparib showed cytotoxic activity in BRCA1 and BRCA2 negative or mutant 


Version 5.0 (30-Aug-2022) 
OU-SCC-PI-4G 
5 
 
cancer cells while sparing the normal cells [17, 18]. More importantly, niraparib could cross the 
blood brain barrier in rodents or mice and inhibited tumor growth in the BRCA2-mutant or non-
mutant intracranial tumor models [6, 7]. 
 
Chornenkyy and colleagues reported the therapeutic potential of PARP1 inhibitors in preclinical 
models of pediatric high-grade astrocytomas (pHGA) and diffuse intrinsic pontine gliomas 
(DIPG) [7]. The positive PARP1 protein expression was found in 28 of 33 pHGA and 13 of 17 
DIPG patient tumor samples. When compared to veliparib and olaparib, niraparib was the most 
effective at reducing In-Vitro cell viability and proliferation [7]. Furthermore, treatment with a 
three-day course of niraparib was sufficient to completely inhibit PARP1 activity in intracranial 
tumor in mice model [7]. Pre-treatment with niraparib could enhance anti-cancer effect of 
ionizing radiation and extended survival of mice bearing orthotopic pHGA xenografts, indicating 
that niraparib may be an effective radiosensitizer for pHGA and DIPG [7]. Similar results were 
reported by Mueller et al showing that niraparib could reduce clonogenicity of neuroblastoma 
cell lines; and combination of niraparib with radiation prolonged survival of murine model 
bearing metastatic neuroblastoma [19]. Interestingly, niraparib mediated radiosensitization was 
selective to cancer cell lines but not for normal cell lines [20].  
 
A recent study by Sulkowski, et al., identified that the isocitrate dehydrogenase 1 (IDH1) and 
IDH2 mutations induce a homologous recombination (HR) defect that would render tumor cells 
sensitive to PARP inhibitors [21].  The IDH mutations are primarily present in Grade II and III 
gliomas, but can also be seen in Grade IV glioblastoma.  Inevitably, the vast majority of Grade II 
and III gliomas will recur and progress to a higher grade at which time there are few therapeutic 
options.  Given this intrinsic deficit in HR, it is likely that gliomas will respond well to PARP 
inhibition in clinical practice.  Previous trials may not have been successful because (1) the 
PARP inhibitor did not cross the blood brain barrier and (2) they did not target the 
subpopulations of gliomas that are more responsive because they have deficits in HR. 
 
Several clinical studies have reported the safety and efficacy of niraparib for the treatment of a 
variety of advanced solid tumors, including primary or secondary brain tumors [2, 22, 23]. A 
phase I dose escalation trial of niraparib demonstrated significant antitumor activity in BRCA 
mutant and sporadic cancers within a large therapeutically effective dosing window (60–300 
mg/day); and established 300 mg/day as the maximum tolerated dose (MTD) [22]. Among 100 
patients enrolled, dose-limiting toxicities reported in the first cycle were one grade 3 fatigue 
(30mg/day), one grade 3 pneumonitis (60 mg/day) and two grade 4 thrombocytopenia 
(400mg/day). Ten of 24 patients with BRCA1 or BRCA2 mutation achieved partial tumor 
response. In addition, anti-cancer activity was also reported in 17 of 48 patients with sporadic 
cancer including high-grade serous ovarian cancer, non-small-cell lung cancer, and prostate 
cancer [22]. A phase I trial of niraparib plus temozolomide reported that niraparib at 40 mg/day 
continuously in combination with 150 mg/m2/day Temozolomide was considered as the MTD 
and demonstrated antitumor activity, with one glioblastoma patient achieved a partial response 
after six treatment cycles of niraparib (40 mg) [24]. The U.S. Food and Drug Administration 
(FDA) has approved niraparib (ZEJULA, GSK, Inc.) for the maintenance treatment of adult 
patients with recurrent platinum-sensitive ovarian, fallopian tube, or primary peritoneal cancer.  


Version 5.0 (30-Aug-2022) 
OU-SCC-PI-4G 
6 
 
 Summary of Investigational Drug 
1.4.1 Pharmacology of Niraparib 
Niraparib is a potent, orally active PARP1 and PARP2 inhibitor being developed as a treatment 
for patients with tumors that harbor defects in the HR DNA repair pathway or that are driven by 
PARP-mediated transcription factors. 
 
1.4.2 Non-clinical Study of Niraparib 
Nonclinical data on niraparib are discussed in detail in the Investigator’s Brochure. Briefly, in 
nonclinical models, niraparib has been observed to inhibit normal DNA repair mechanisms and 
induce synthetic lethality when administered to cells with HR defects. In a BRCA1-mutant 
xenograft study, niraparib dosed orally caused tumor regression, which was mirrored by > 90% 
reduction in tumor weight compared with control. In a BRCA2-mutant xenograft study, niraparib-
dosed mice showed 55% to 60% growth inhibition, both by tumor volume and weight. 
Niraparib displayed strong antitumor activity in in vivo studies with BRCA1-mutant breast cancer 
(MDA-MB-436), BRCA2-mutant pancreatic cancer (CAPAN-1), ATM-mutant mantle cell 
lymphoma (GRANTA-519), serous OC (OVCAR3), and colorectal cancer (HT29 and DLD-1) 
xenograft models and with patient-derived Ewing sarcoma mice models. Utilizing patient-derived 
ovarian and breast cancer xenograft models, niraparib demonstrated response in both BRCA 
mutation and BRCA wild-type tumors. 
 
1.4.3 Clinical Safety of Niraparib 
Niraparib clinical data are discussed in detail in the niraparib IB. In the Phase 1 clinical program, 
niraparib, as a monotherapy or in combination with chemotherapy, has been administered to 
144 patients. 
 
Phase 1 Study of Niraparib Monotherapy in Advanced Solid Tumors 
Niraparib clinical data are discussed in detail in the niraparib IB. In the Phase 1 clinical program, 
niraparib, as a monotherapy or in combination with chemotherapy, has been administered to 
144 patients. 
 
Phase 1 Study of Niraparib Monotherapy in Advanced Solid Tumors 
Clinical activity data for niraparib administered as monotherapy in patients with ovarian cancer 
are available from 1 early-phase clinical study. In Parts A and B of the Phase 1 study PN001 
(ClinicalTrials.gov identifiers: MK-4827-001 and 2008_501), 100 patients with advanced solid 
tumors who had received a median of 3 prior therapies were enrolled; 49 patients had ovarian 
cancer (13 platinum-sensitive, 35 platinum-resistant, and 1 platinum-refractory).[22] An 
additional 4 patients were enrolled in Part D of the study, which assessed pharmacokinetics 
only.  
The most common nonhematological TEAEs were nausea, fatigue, anorexia, constipation, 
vomiting, and insomnia. These TEAEs were mainly mild to moderate in severity, self-limiting, 
and manageable with standard treatments. Hematological toxicity appeared to be dose 
proportional and most frequently arose in the setting of cumulative doses. Anemia was reported 
in 48 (48%) of 100 patients and was Grade ≥3 in 10 (10%) of 100 patients. Thrombocytopenia 
was less common (35 [35%] of 100 patients) and was Grade ≥3 in 15 (15%) of 100 patients. 


Version 5.0 (30-Aug-2022) 
OU-SCC-PI-4G 
7 
 
Neutropenia was the least commonly reported (24 [24%] of 100 patients), and was Grade 3 in 4 
(4%) of 100 patients at niraparib doses of 300 and 400 mg. In all cases, hematological TEAEs 
were uncomplicated and reversible. Twenty patients required dose reductions (usually by 1 
dose level) for recurrent anemia or thrombocytopenia. Treatment was discontinued due to AEs 
in 7 patients, including the 4 patients who had DLTs during the first cycle and 3 patients who 
had Grade 3 vomiting, Grade 2 prolongation of QT interval, and Grade 3 prolongation of QT 
interval. No treatment-related deaths occurred. 
Of the 49 patients, 22 had confirmed BRCA1 or BRCA2 mutation, of whom 20 were 
radiologically assessable. Eight (40%) of these 20 patients achieved a confirmed partial 
response (PR) by Response Evaluation Criteria in Solid Tumors (RECIST) and cancer antigen 
125 (CA 125) Gynecologic Cancer Intergroup criteria at doses ranging from 80 to 400 mg per 
day. Median response duration was 387 days (range: 159 to 518 days). Three (33%) of 9 
patients with platinum-resistant BRCAmut ovarian cancer had PR by RECIST and CA-125 
criteria. In patients with platinum-sensitive disease, 5 (50%) of 10 patients (95% CI: 19 to 81) 
with BRCA1 or BRCA2 mutations had RECIST and CA-125 responses. 
 
Please refer to Niraparib IB for more details.  
 
1.4.4 Clinical Efficacy of Niraparib 
Clinical activity data for niraparib administered as monotherapy or combination therapy in 
patients with various cancer are discussed in detail in the niraparib Investigator’s Brochure 
v11.0.  
 
1.4.5 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 baseline platelets had an impact on 
platelet nadir; lower baseline platelets (<180 109/L) 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 


Version 5.0 (30-Aug-2022) 
OU-SCC-PI-4G 
8 
 
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%).  
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.  
 
 Rationale for this study 
Patients with primary brain cancer have a poor prognosis and few effective treatment options. 
Niraparib crossed the blood brain barrier and inhibited intracranial tumor growth in animal 
models [6, 7]. In addition, niraparib could mediate radio-sensitization selective to cancer cell 
lines but not for normal cell lines [20]. Furthermore, loss of PTEN (phosphatase and tensin 
homologue) was found in 70% of GBM patients, with somatic mutations occurring in 25–40% of 
cases [28]; cancers with PTEN loss or homologous recombination deficiency are sensitive to 
PARP inhibitors [29, 30]. We anticipate that Niraparib can cross the blood-brain barrier and 
produce anti-cancer effect on patients with GBM. Our study plan is to conduct a safety lead-in 
with individualized starting dose (ISD) , followed by dose expansion study to determine the 
safety and efficacy of niraparib for patients with recurrent brain tumor. The patient’s tumor will 
be evaluated for the presence of IDH1 and IDH2 as they could contain intrinsic HR defects.  
 
 STUDY OBJECTIVES AND ENDPOINTS 
2.1 Study Objectives 
2.1.1 Co-primary Objectives: 
• 
For safety lead-in phase: To evaluate the safety and tolerability of niraparib using 
individualized starting dose (ISD) in patients with recurrent brain tumor.   
• 
For Phase II Dose Expansion Cohorts: To evaluate the efficacy (monitored by 
disease control rate; DCR) of niraparib in patients with recurrent brain tumor using 
Response Assessment in Neuro-Oncology Criteria (RANO); and to evaluate the 
safety of niraparib in patients with recurrent brain tumor at safety lead-in dose.   
 
2.1.2 Secondary Objectives: 
• 
To evaluate Progression free survival (PFS) and overall survival (OS) time for 
patients enrolled in dose expansion cohorts. 


Version 5.0 (30-Aug-2022) 
OU-SCC-PI-4G 
9 
 
• 
To evaluate the duration of disease control (DDC) in patients enrolled on study.  
 
2.1.3 Exploratory Objectives: 
• 
To identify potential biomarkers associated with tumor response to niraparib based 
on the molecular profile of tumor tissue biomarkers. 
• 
To correlate homologous recombination deficiency (HRD)  score obtained via 
myChoice test (Myriad Genetics) with other biomarkers such as IDH1/IDH2 mutation 
and with treatment outcomes. 
 
2.2 Study Endpoints 
2.2.1 Co-Primary Endpoints: 
• 
For safety lead-in dose and expansion cohorts, monitor safety and tolerability of 
niraparib with individualized starting dose (ISD) in patients with recurrent brain tumor. 
Determination of safety will utilize adverse event occurrence monitoring and grade 
using CTCAE v5.0. 
• 
For Phase II dose expansion cohorts, define the anti-cancer efficacy of niraparib in 
patients with recurrent brain tumor by disease control rate (DCR; complete and 
partial response, and stable disease) as assessed by the RANO. DCR is the 
percentage of patients with a SD or better from start of treatment (cycle 1, day 1) to 3 
months, 6 months, 9 months, and 12 months per RANO.  
 
2.2.2 Secondary Endpoints: 
• 
Anticipate to have prolonged PFS and OS for patients enrolled in dose expansion 
cohorts 
• 
DDC is elapsed time from the first documented CR, PR, pathological CR, or SD until 
first documentation of disease progression or death, whichever comes first. 
 
2.2.3 Exploratory Endpoints: 
• 
Obtain preliminary data about the molecular profile of tumor tissue biomarkers and 
their association with tumor response to niraparib.  
• 
Obtain preliminary data about the association of HRD status with other biomarkers 
and with the anti-cancer effect of niraparib. 
 
 INCLUSION / EXCLUSION CRITERIA 
3.1 Inclusion Criteria  
1. Patients must be able to understand and willing to sign the informed consent form. 
2. Patients must be ≥ 18 years of age.    
3. Patients must have histologically proven high grade gliomas - GBM, Astrocytoma, or 
Oligodendroglioma (glioma WHO Grade III or IV) that is now recurrent by MRI or 
surgical pathology. If there is clinical evidence (such as MRI contrast enhancement) 
that supports a Grade 3 diagnosis of the glioma, the patient will be eligible for the 
study (even if the initial diagnosis was a Grade 2).  
4. Patients must have measurable or evaluable lesions by RANO.  
5. Eastern Cooperative Oncology Group (ECOG) performance status of 0-2 


Version 5.0 (30-Aug-2022) 
OU-SCC-PI-4G 
10 
 
6. Patient has archival tumor tissue available; or a fresh biopsy of recurrent or 
persistent tumor must be obtained for molecular assay by myChoice test (Myriad 
Genetics) prior to study treatment initiation. Patient will be requested to share reports 
from any prior genetic testing with the study investigators.  
7. Participants have systolic BP< 140 mmHg or diastolic BP <90 mmHg that has been 
adequately treated or controlled. 
8. Have adequate organ function defined by ANC > 1500 cells/mcl, platelets > 
100,000/mcl, Hemoglobin ≥ 9 g/dL, calculated creatinine clearance ≥ 50  mL/min (by 
Cockcroft-Gault formula); total bilirubin < 1.5 times ULN, alanine aminotransferase 
(ALT) and aspartate aminotransferase (AST) levels < 2.5 x ULN.  
9. Be able to take oral medications  
10. Life expectancy ≥ 3 months, allowing adequate follow up of toxicity evaluation and 
antitumor activity; 
11. Female patient, if of childbearing potential, has a negative serum pregnancy test 
within 72 hours of taking study medication and agrees to abstain from activities that 
could result in pregnancy from enrollment through 180 days after the last dose of 
study treatment or is of nonchildbearing potential. Nonchildbearing potential is 
defined as follows (by other than medical reasons): 
• 
≥45 years of age and has not had menses for >1 year 
• 
Patients who have been amenorrhoeic for <2 years without history of a 
hysterectomy and oophorectomy must have a follicle stimulating hormone 
value in the postmenopausal range upon screening evaluation 
• 
Post-hysterectomy, post-bilateral oophorectomy, or post-tubal ligation. Verbal 
confirmation of hysterectomy, oophorectomy, or tubal ligation from the patient 
of non-childbearing potential to study staff is sufficient in lieu of records from 
actual procedure and/or confirmation by ultrasound. In this case, the patient 
must be willing to use two adequate barrier methods throughout the study, 
starting with the screening visit through 180 days after the last dose of study 
treatment. This information must be captured appropriately within the site’s 
source documents. Note: Abstinence is acceptable if this is the established 
and preferred contraception for the patient. 
12. Male participant agrees to use an adequate method of contraception starting with the 
first dose of study treatment through 180 days after the last dose of study treatment. 
Note: Abstinence is acceptable if this is the established and preferred contraception 
for the patient. 
In addition, men must not donate sperm during niraparib therapy and for 90 days 
after receiving the last dose of niraparib. 
13. Patient must agree to not breastfeed during the study or for 30 days after the last 
dose of study treatment. 
14. Participant must agree to not donate blood  during the study or for 90 days after the 
last dose of study treatment. 
15. Participant receiving systemic corticosteroids may continue as long as their dose is 
stable for at least 4 weeks prior to initiating protocol therapy. Topical and nasal 
steroids are not considered contraindicative and may be used.  


Version 5.0 (30-Aug-2022) 
OU-SCC-PI-4G 
11 
 
 
3.2 Exclusion Criteria 
1. Patient has a known additional malignancy that progressed or required active 
treatment within the last 3 years (exceptions include basal cell carcinoma of the skin, 
squamous cell carcinoma of the skin that has undergone potentially curative therapy, 
or in situ cervical cancer). 
2. Prior treatment with a known poly(ADP-ribose) polymerase (PARP) inhibitor 
3. Participants with human immunodeficiency virus (HIV) with detectable viral load. 
Participants with HIV on effective anti-retroviral therapy with documented 
undetectable viral load and CD4 count ≥ 350 within 6 months of the first dose of study 
treatment are eligible for this trial.  
4. Known active hepatitis B or hepatitis C. 
5. Known history of myelodysplastic syndrome (MDS) or acute myeloid leukemia (AML). 
6. Participant is pregnant or expecting to conceive  while receiving study treatment 
and/or for up to 180 days after the last dose of study treatment. 
7. Patient currently participating and receiving study therapy or has participated in a 
study of an investigational agent and received study therapy or used an 
investigational device within 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 dose of study 
drug. 
8. Received prior anticancer therapy (chemotherapy, targeted therapies, radiotherapy, 
or immunotherapy) within 4 weeks.  
9. Patients must not have a known hypersensitivity to the components of niraparib or 
the excipients (lactose monohydrate and magnesium stearate).  
10. Patients must not have had major surgery within 4 weeks (including craniotomy) of 
starting the study and patient must have recovered from any effects of any major 
surgery. Stereotactic biopsy by burr hole is considered a minor surgery, and those 
patients undergoing this surgery will be eligible for the study 2 weeks post-procedure.   
11. Patients must not have had radiotherapy encompassing > 20% of the bone marrow 
within 2 weeks; or any radiation therapy within 1 week prior to Day 1 of protocol 
therapy. 
12. Patients must not have received a transfusion (platelets or red blood cells), colony 
stimulating factors (eg, granulocyte colony-stimulating factor, granulocyte 
macrophage colony stimulating factor, or recombinant erythropoietin) ≤ 4 weeks of 
the first dose of study treatment. 
13. Patient has had any known Grade 3 or 4 anemia, neutropenia or thrombocytopenia 
due to prior chemotherapy that persisted > 4 weeks and was related to the most 
recent treatment.  
14.  Participants have any clinically significant gastrointestinal abnormalities that may 
alter absorption such as malabsorption syndrome or major resection of the stomach 
and/or bowels.   
15. Participants have received live vaccine within 30 days of planned start of study 
randomization. 


Version 5.0 (30-Aug-2022) 
OU-SCC-PI-4G 
12 
 
16. Patients have 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, or any psychiatric disorder that prohibits 
obtaining informed consent 
17. Any medical condition not yet specified above that is considered to possibly, probably 
or definitely interfere with study procedures, including adequate follow-up and 
compliance and/or would jeopardize safe treatment. 
 
 SUBJECT REGISTRATION AND ENROLLMENT   
4.1 Required protocol specific regulatory documents   
This protocol, the Informed Consent document, any information to be given to the 
patient, and relevant supporting information must be submitted to the IRB by the 
Principal Investigator and reviewed and approved by the IRB before the study is 
activated by the Sponsor.  
 
The Sponsor must pre-approve the informed consent document prior to submission to 
the IRB. All regulatory documents must be available to the Sponsor prior to site 
activation. Before the study can be initiated at any site, the following documentation 
must be provided to Stephenson Cancer Center Clinical Trials Office (SCC CTO): 
• 
A copy of the IRB approval letter 
• 
CV and medical licensure for the principal investigator 
• 
Form FDA 1572 appropriately completed and signed 
• 
A copy of the IRB-approved consent form 
• 
CAP and CLIA Laboratory certifications and institution lab normal values 
• 
Executed clinical research contract 
 
4.2 Patients Registration and Enrollment 
Sites must confirm with The University of Oklahoma Stephenson Cancer Center (OU-
SCC) that a slot is available before proceeding with consenting any patient. A Screening 
identification (Screening ID) number will be provided by OU-SCC research staff after the 
patient has been consented.  After all screening procedures and assessments have 
been completed, the study site should complete the Subject Enrollment Form and send 
along with the required documentation to DataIntegrity@ouhsc.edu, for confirmation of 
eligibility. The Study ID number will be generated by OU-SCC once eligibility has been 
confirmed. Once the patient has been provided a Study ID number, only the Study ID 
number should be used.  
 
Patients must not start protocol treatment prior to enrollment. Patients will start protocol 
treatment only after pre-treatment evaluation is complete and eligibility criteria have 
been met. 
 


Version 5.0 (30-Aug-2022) 
OU-SCC-PI-4G 
13 
 
NOTE: Per the Institutional Review Board (IRB) reporting, a patient is considered 
accrued once he or she signs a consent form for the study. A patient is 
considered enrolled once the patient begins treatment. Evaluable patients are 
defined in protocol Section 10.1.  
 
 SCHEMA AND TREATMENT PLAN 
5.1 Schema  
 
 
 
 
 
 
 
 
 
 
^ Up to six patients may be enrolled in the safety lead-in phase. See Section 6.1 for details.  
* Up to 42 patients may be enrolled in the dose expansion phase. Total patients will be 45. See 
Section 6.1 for details. 
5.2 Study Treatment 
This is a single arm phase II trial of niraparib in patients with recurrent gliomas. Three to six 
patients will be enrolled in the safety lead-in phase with ISD. If no AEs are observed in the first 3 
patients, they will be included in the dose expansion phase of the study. If 1/3 patients 
experiences an AE that is determined to be significant by the PI and medical monitor, the same 
dose will be expanded to 3 more patients. A safety review will be conducted following the 
treatment of the first three or all six patients to determine the niraparib dose for the dose 
expansion phase. Patients enrolled in the safety lead-in phase will be included in the dose-
expansion phase. The starting dose of niraparib for the safety lead-in phase will depend on 
baseline platelet count and weight as summarized in Table 1.   
 
Table 1 Niraparib Invidualized Starting Dose (ISD)   
Baseline Criteria  
Starting Dose  
≥77 kg and ≥150,000 µL 
300 mg (3 X 100 mg capsules) daily  
<77 kg or <150,000 µL 
200 mg (2 X 100 mg capsules) daily* 
 
Recurrent GBM,  or 
Astrocytoma or 
Oligodendroglioma 
with measurable 
lesion; 
Pre-treatment tumor 
assessment (archival 
tissue or fresh tissue 
from recent surgery)  
molecular profile, 
HRD & other studies. 
 
Safety lead-in 
with 
Individualized 
starting dose 
(ISD)^    
Niraparib 
(starting at 
ISD: 300 mg 
or 200 mg) 
PO, QD, Days 
1-28 (28 days 
per cycle) 
Dose 
Expansion 
with ISD*  
Niraparib 
(starting at 
ISD: 300 mg 
or 200 mg) 
PO, QD, Days 
1-28 (28 days 
per cycle) 
Treatment 
Discontinuation for 
Toxicity 
Tumor progression 
(for SOC), collection 
of pathology tissue 


Version 5.0 (30-Aug-2022) 
OU-SCC-PI-4G 
14 
 
*For patients whose starting dose in the dose expansion phase starts at 2 capsules once daily, 
their dose will remain at the same level if there are no indications to reduce the dose. There will 
be no planned increase in the dose even if the patient tolerates it well.  
5.3 Treatment Plan  
5.3.1 Niraparib Dose for Safety Lead-in Phase:  
Three to six patients will be enrolled in the safety lead-in phase utilizing ISD. The starting 
dose will be 300 mg niraparib (or modified according to Table 1), taken orally once a day for 
the first cycle of 28 days. The safety review will be conducted following the safety lead-in 
phase to review AEs, and the dosage for the dose expansion phase will be accordingly 
modified if required. 
5.3.2 Niraparib Dose for Phase II Dose expansion cohort:  
Niraparib will be continued to be administered at ISD (Table 1) on days 1-28 per 28 day 
cycle, or dosage will be modified based on safety review recommendations after the safety 
lead-in phase. See Section 7.1.3 for dose administration.    
 
5.4 Dose Modification 
Study treatment dosing interruptions are permitted in the case of medical/surgical events or 
logistical reasons not related to study therapy (eg, surgery, unrelated medical events, patient 
vacation, and/or holidays). Patients should be placed back on study therapy within 28 days of 
the scheduled interruption, unless otherwise discussed with the Investigators.  
A safety review will be conducted following the safety lead-in phase to review AEs, and 
niraparib dosage for the dose expansion phase will be accordingly modified if required. Dose 
reduction of niraparib may be implemented per the Investigator’s judgement in patients enrolled 
in safety lead-in phase cohort and at any time in patients enrolled in phase II dose expansion 
cohort.  
All treatment interruptions and dose reductions (including any missed doses), and the reasons 
for the reductions/interruptions, are to be recorded in the electronic case report form (eCRF). 
5.4.1 Dose Modifications for Non-Hematologic Toxicity 
Treatment with niraparib must be interrupted for any treatment-related non-hematologic CTCAE 
Grade 3 or 4 event. Once resolved to Grade ≤ 1, the patient may restart treatment with niraparib 
with a dose level reduction (see Table 2) unless prophylaxis is considered feasible. If the event 
recurs at a similar or worse grade, treatment should be interrupted again and, upon resolution, a 
further dose reduction must be made to a lower dose level, if available, or niraparib dosing 
should be discontinued. If the toxicity requiring dose interruption has not resolved to CTCAE 
Grade ≤ 1 during a maximum 4-week (28-day) dose interruption period, and/or the patient has 
already undergone a maximum of 2 dose reductions (to a minimum dose of 100 mg QD), the 
patient must permanently discontinue treatment with niraparib.  
 
 


Version 5.0 (30-Aug-2022) 
OU-SCC-PI-4G 
15 
 
Table 2 Niraparib Dose Reductions for Non-Hematologic Toxicity 
Event 
Dose 
 
100 mg QD, Day 
1-28 
200 mg QD, Day 
1-28 
300 mg QD, Day 1-
28 
1st dose reduction for 
treatment-related adverse 
reactions CTCAE ≥ Grade 3 
where prophylaxis is not 
considered feasible or 
adverse reaction event 
persists despite treatment 
N/A a 
100 mg, QD, Day 
1-28 
200 mg QD, Day 1-
28 
2nd dose reduction b for 
treatment-related CTCAE 
Grade 3 or 4 AE or 
SAE where prophylaxis is not 
considered feasible or 
adverse reaction event 
persists despite treatment  
N/A 
N/A 
100 mg QD, Day 1-
28 
Continued treatment-related 
CTCAE Grade 3 or 4 AE or 
SAE 
≥ 28 days 
Discontinue 
niraparib  
Discontinue 
niraparib 
Discontinue 
niraparib 
Abbreviations: AE = adverse event; CTCAE = Common Terminology for Adverse Events; QD = once 
daily; SAE = serious adverse event. 
a. Dose not to be decreased below 100 mg daily, day 1-28. 
b. If initial dose is below 300 mg, the same dose reduction principles will apply with fewer dose 
modification steps available. 
5.4.2 Dose Modifications for Hematologic Toxicity 
Table 3 Management of Hematologic Toxicities 
Laboratory Abnormality 
Intervention 
Monitor complete blood counts (CBC) weekly for the first two months (two cycles), monthly for 
the next 11 months of treatment, and periodically after this time. 
Platelet count <100,000/µL 
Niraparib must be interrupted for a maximum of 28 days 
until platelet count is ≥ 100,000/μL with weekly CBC 
monitored until recovery. Niraparib may then be resumed at 
same dose. After recovery, blood counts once weekly for 4 
weeks. If platelet count is <75,000/µL, resume at a reduced 
dose. 


Version 5.0 (30-Aug-2022) 
OU-SCC-PI-4G 
16 
 
Further occurrence of platelet 
count <100,000/µL 
Niraparib must be interrupted for a maximum of 28 days 
until platelet count is ≥ 100,000/μL with weekly CBCs 
monitored until recovery. Niraparib may then be resumed at 
a reduced dose (see Table 2); after recovery, blood counts 
once weekly for 4 weeks. A further dose reduction should be 
made if an additional treatment interruption is needed after 
resuming treatment. 
Discontinue niraparib if the platelet count has not returned to 
acceptable levels (≥ 100,000/μL) within 28 days of the dose 
interruption period, or if the patient has already undergone 
dose reduction to 100 mg QD. 
Platelet count < 75,000/μL 
Withhold niraparib for a maximum of 28 days and monitor 
blood counts weekly until platelet counts return to 
≥100,000/μL.  
Resume niraparib at a reduced dose. Dose will be 
maintained at reduced dose as long as platelet counts are 
trending upward, and considered minimal risk by treating 
physician.  
Discontinue niraparib if the platelet count has not returned to 
acceptable levels (≥ 100,000/μL) within 28 days of the dose 
interruption period, or if the patient has already undergone 
dose reduction to 100 mg QD, day 1-28.  
Neutrophil < 1,000/μL 
Niraparib must be interrupted until neutrophil counts are ≥ 
1,000/μL with weekly CBCs monitored until recovery within 
28 days. Niraparib may then be resumed at a reduced dosea 
(see Table 2); after recovery, blood counts once weekly for 
3 weeks to ensure the safety of the new dose level. 
Discontinue niraparib if neutrophil level has not returned to 
acceptable levels (≥ 1,000/μL) within 28 days of the dose 
interruption period, or if the patient has already undergone 
maximum dose reductions. 
Hemoglobin ≤ 8 g/dL 
Niraparib must be interrupted until hemoglobin is > 8 g/dL 
with weekly CBCs monitored until recovery within 28 days. 
Niraparib may then be resumed at a reduced dose (see 
Table 2); after recovery, blood counts once weekly for 3 
weeks to ensure the safety of the new dose level. 
Discontinue niraparib if hemoglobin has not returned to 
acceptable levels (≥ 8 g/dl) within 28 days of the dose 
interruption period, or if the patient has already undergone 
maximum dose reductions. 


Version 5.0 (30-Aug-2022) 
OU-SCC-PI-4G 
17 
 
Hematologic adverse reaction 
requiring transfusion or 
hematopoietic growth factor 
support 
For patients with platelet count ≤10,000/μL, platelet 
transfusion should be considered. If there are other risk 
factors such as co-administration of anticoagulation or 
antiplatelet drugs, consider interrupting these drugs and/or 
transfusion at a higher platelet count. 
Resume niraparib at a reduced dose. 
Confirmed diagnosis of MDS* 
or AML† 
Permanently discontinue niraparib. 
*MDS = myelodysplastic syndrome 
†AML = acute myeloid leukemia 
a. Dose not to be decreased below 100 mg daily, day 1-28. 
• 
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. 
• 
Any patient requiring transfusion of platelets or red blood cells (1 or more units) or 
hematopoietic growth factor support must undergo a dose reduction upon recovery if 
study treatment is resumed. 
• 
The patient must be referred to a hematologist for further evaluation (1) if frequent 
transfusions are required or (2) if the treatment-related hematologic toxicities have not 
recovered to CTCAE Grade 1 or less after 4 weeks.  
• 
For major surgery while on treatment, up to 28 days of study treatment interruption is 
allowed.  
• 
Once the dose of study treatment has been reduced, any re-escalation must be 
discussed with the medical monitor. 
• 
All dose interruptions and reductions (including any missed doses), and the reasons for 
the reductions/interruptions, are to be recorded in the eCRF. 
 
5.5 Precaution for Concomitant Medications 
Any medication the patient takes during the study other than the study treatments, including 
herbal and other nontraditional remedies, is considered a concomitant medication. All 
concomitant medications must be recorded in the eCRF. The following information must be 
recorded for each concomitant medication: generic name, route of administration, start date, 
stop date, dosage, and indication. Any changes in the dosage or regimen of a concomitant 
medication must be recorded in the eCRF. 
At screening, patients will be asked what medications they have taken during the last 30 days. 
At each subsequent study visit, patients will be asked what concomitant medications they are 
currently taking or have taken since the previous visit. 
Niraparib weakly induces Cytochrome P450 (CYP)1A2 in vitro and is a relatively poor substrate 
for P-glycoprotein (P-gp); therefore, investigators are advised to use caution with the substrates 
for CYP1A2 with a narrow therapeutic range, i.e. theophylline and tizanidine. Appendix A has a 
more comprehensive lists of CYP1A2 substrates. The niraparib safety profile includes risk for 


Version 5.0 (30-Aug-2022) 
OU-SCC-PI-4G 
18 
 
thrombocytopenia; therefore, investigators should be advised to use caution with 
anticoagulation and antiplatelet drugs. 
 
5.5.1 Prohibited Medications 
Patients are prohibited from receiving the following therapies during the screening and 
treatment phase of this study: 
Antineoplastic systemic chemotherapy or biological therapy 
• 
Any anti-cancer therapy not specified in this protocol, such as Chemotherapy or 
Immunotherapy 
• 
Investigational agents other than niraparib  
• 
Radiation therapy is prohibited if encompassing > 20% of the bone marrow within 2 
weeks or any radiation therapy within 1 week prior to study Day 1. 
Note: The following may be considered exceptions on a case-by-case basis after 
consultation with the Sponsor: Radiation therapy to pre-existing small areas of painful 
metastases that cannot be managed with local or systemic analgesics (excluding 
palliative radiotherapy encompassing > 20% of the bone marrow) as long as no 
evidence of disease progression is present. The patient must have clear measurable 
disease outside the radiated field. Administration of palliative radiation therapy may be 
considered clinical progression for the purposes of determining PFS. 
• 
The patient can receive a stable dose of corticosteroids during the study as long as their 
dose is stable for at least 4 weeks prior to initiating protocol therapy. 
Note: Inhaled steroids are allowed for the management of asthma. 
• 
Live vaccines within 30 days prior to the first dose of study treatment and while 
participating in the study. The combination of niraparib with live vaccines or 
immunosuppressant agents has not been studied.  Inactive vaccines are permitted. 
• 
Prophylactic cytokines (G-CSF) should not be administered in the first cycle of the study 
but may be administered in subsequent cycles.  
If there is a clinical indication for any medication or vaccination specifically prohibited during the 
study, discontinuation from study therapy may be required. The final decision on any supportive 
therapy or vaccination rests with the Investigator and/or the patient’s primary physician. The 
decision to continue the patient on study therapy, however, requires the mutual agreement of 
the Investigator, the Sponsor, and the patient. 
 
5.5.2 Study Restrictions 
Participants of childbearing potential who are sexually active and their partners must agree to 
the use of a highly effective form of contraception throughout their participation beginning with 
time of consent, during the study treatment and for 180 days after last dose of study 
treatment(s): 
• 
Combined (estrogen and progestogen containing) hormonal contraception 
associated with inhibition of ovulation: 
− 
Oral route 
− 
Intravaginal route 
− 
Transdermal route 


Version 5.0 (30-Aug-2022) 
OU-SCC-PI-4G 
19 
 
• 
Progestogen-only hormonal contraception associated with inhibition of ovulation  
− 
Oral 
− 
Injectable 
− 
Implantable 
• 
Intrauterine device 
• 
Intrauterine hormone-releasing system 
• 
Bilateral tubal occlusion 
• 
Vasectomized partner 
• 
Sexual abstinence, if the preferred and usual lifestyle of the subject 
In addition, men must not donate sperm during niraparib therapy and for 180 days after 
receiving the last dose of niraparib. 
 
5.6 Breast Feeding 
Patients must not breast-feed from the time they receive the first dose of niraparib and for 180 
days following the final dose of niraparib. 
 
5.7 Blood Donation 
Patients must not donate blood during the study or for 90 days after the last dose of study 
treatment. 
 
5.8 Supportive Care 
All supportive measures consistent with optimal patient care will be given throughout the study. 
 
5.9 Duration of Therapy 
Patients will be treated until disease progression or toxicity unless patient withdraws consent or 
in the event of severe noncompliance. 
 
5.10 
Duration of Follow-up 
For this protocol, all patients, including those who discontinue protocol therapy early, will be 
followed for response until progression, and for two years from the end of treatment to assess 
for MDS/AML and overall survival. All patients must also be followed through completion of all 
protocol therapy. 
 
 STUDY DESIGN AND PARAMETERS  
 
6.1 Study Design 
This phase II study will utilize a safety lead-in with an individualized starting dose (ISD) strategy, 
wherein up to six patients may be treated with 200 mg or 300 mg, PO, QD of niraparib on days 
1-28. In order to adequately assess safety data by the conclusion of this phase, three patients 
will be treated with the study drug and adverse events (AEs) will be assessed in the first 28 
days of treatment, i.e., one treatment cycle of niraparib. The study will continue to the dose 
expansion phase (with inclusion of the first three patients), unless there are Grade 4 
hematological, or Grade 4 non-hematological toxicities (as per CTCAE v5.0) that are unresolved 


Version 5.0 (30-Aug-2022) 
OU-SCC-PI-4G 
20 
 
after 4 weeks, or SUSARs (Suspected Unexpected Serious Adverse Reaction) on the study. If 
1/3 patients experience any of the above, the same dose will be expanded to three more 
patients, and another safety review may be conducted following the treatment of all six patients 
to determine the niraparib dose for the dose expansion phase. The starting dose of niraparib for 
the safety lead-in phase will depend on baseline platelet count and weight as summarized in 
Table 1.  
 
No intra-patient dose escalations are allowed. No further dose escalation will be conducted 
even if no SAEs are observed with either starting dose (either 200 mg or 300 mg) in the first 
cycle of treatment. If the starting dose for the patient is 300 mg, the dose can be decreased to 
either 200 mg or 100 mg depending on the severity of the AE. If the starting dose is 200 mg, the 
dose can be decreased to 100 mg. Refer to Table 2 for more details. No dose reduction to less 
than 100 mg niraparib QD, will be permitted. AEs observed at the 100 mg does level of 
niraparib, will be managed according to Table 3 in the protocol. Only clinically significant AEs 
will require change to patient treatment.  
 
6.2 Study Parameters 
6.2.1 Therapeutic Parameters  
1. 
Pre-study scans should be performed within 4 weeks prior to registration.  
2. 
All required pretreatment laboratory studies should be done as outlined in the study 
calendars in Section 6.2.2.    
3. 
Initial H&P and laboratory tests performed during screening can be used for C1D1 if 
done within 7 days.  
 
 


Version 5.0 (30-Aug-2022) 
OU-SCC-PI-4G 
21 
 
6.2.2 Study Calendar 
Table 4 lists the schedule of events for screening and safety monitoring.    
Table 4 Schedule of Events 
Cycles 
Screening 
Cycle 1 and 2 a 
  
Subsequent 
Cycles a 
EOT 
Follow
-Up l 
Post-
Treatment  
 
Day 
-28 to 
-1 
Day 1 
(-3 
days) 
Day 8 
(± 3 
days) 
Day 15 
(± 3 
days) 
Day 22 
(±3 
days) 
Day 1 of each 
cycle (+/- 3 
days) 
 
 
Every 12 
weeks 
Informed Consent 
X 
 
 
 
 
 
 
 
 
Inclusion/ exclusion 
criteria review 
X 
X 
 
 
 
 
 
 
 
History & Physical 
X 
Xb 
 
 
 
 
 
 
 
ECOG-PS 
X 
Xb 
 
 
 
X 
X 
X 
 
Vital signs & weight b 
X 
X 
X 
X 
X 
X 
X 
X 
 
Toxicity assessment 
X 
X 
 
X 
X 
X 
X 
X 
X 
CBC/Diff/ Plts c 
X 
Xb 
Xc 
Xc 
Xc 
X 
X 
 
 
Serum chemistryd 
X 
Xb 
 
X 
X 
X 
X 
 
 
PT /PTT /INR 
X 
 
 
X 
X 
 
X 
 
 
Urinalysis 
X 
Xb 
 
 
 
X 
X 
 
 
Serum pregnancy 
test e 
X 
 
 
 
 
X 
X 
 
 
MRI / CT f 
X 
 
every 8 weeks (± 7 days) 
 
X  
Tumor tissue 
Xg 
 
 
 
 
 
Xh 
 
 
Niraparib dispensed/ 
Accountability 
 
X 
 
 
 
X 
X 
 
 
Adverse Event 
Monitoring i 
 
X -------------------- X 
Survival assessment 
 
 
 
 
 
 
 
 
X j 
Follow-up for 
MDS/AML 
 
 
 
 
 
 
 
 
X 
Bone marrow 
aspirate and biopsy 
for cytogenetic 
analysis 
 
 
 
If clinically indicated X k 
a. Treatment cycles are 28 days long, with visits on Day 1 of each cycle unless otherwise specified. 
Visits (other than Cycle 1) continue every 28 days until study treatment discontinuation. All visits have 
a window of ± 3 days (calculated in reference to Cycle 1/Day 1). 
b. If history, PE, ECOG-PS and screening laboratory tests are performed within 7 days prior to first dose 
(Cycle 1, Day 1), repeat testing is not required. Only blood pressure and heart rate will be monitored 
weekly for the first 2 cycles then at the start of each new cycle and periodically thereafter during 
treatment with niraparib. Respiratory rate, temperature, and weight are not required weekly for the 
first two cycles, only on Day 1 of each cycle.  
c. Weekly blood draws will be performed for the first cycle (28 days), monthly for the next 11 months of 
treatment, and periodically thereafter. If dose interruption or modification is required at any point on 
study because of hematologic toxicity, weekly 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 


Version 5.0 (30-Aug-2022) 
OU-SCC-PI-4G 
22 
 
weeks after the AE has been resolved to the specified levels, after which monitoring every 4 weeks 
may resume. 
d. Consisting of albumin, alkaline phosphatase, BUN, calcium, carbon dioxide (CO2), chloride, 
creatinine, glucose, potassium, AST, ALT, sodium, total bilirubin, total protein. 
e. Female subjects of childbearing potential as defined in the eligibility criteria must have a serum or 
urine beta-hCG pregnancy test within ≤ 72 hours prior to initiating protocol therapy, approximately 
every  month at End of Treatment and until 180 days after the last dose. FSH level screening may be 
performed to determine if it is in the postmenopausal range.  
f. 
RANO tumor assessment via Brain-MRI or CT will be required at screening, every 8 weeks (± 7 days; 
but it can be evaluated in a case by case basis) from Cycle 1/Day 1 for 6 months, and then every 12 
weeks until progression. If MRI schedule for the patient is changed for clinical purposes, this regimen 
will be altered to avoid duplicate scans, but ensure one is taken at least every 3 months.  
g. Tumor tissues should be collected at screening (either archival tissue or fresh biopsy if recent surgery 
has been performed is also permitted).  
h. Tumor tissue collection at EOT will be optional (obtained if part of standard of care) 
i. 
AEs should be monitored for at least 30 days post last dose or until the AE / SAE has resolved, until 
any abnormal laboratory values have returned to baseline or normal levels, until stabilized with a 
satisfactory explanation for the changes observed, until the patient is lost to follow-up, or until the 
patient has died. If an Investigator becomes aware of an SAE after the specified follow up period and 
considers the SAE related to the study drug, the Investigator should report the SAE to the Sponsor 
and GSK according to timelines for reporting SAEs. SAE and AESI (adverse event of special interest) 
reporting is outlined in Section 9.0.   
j. 
For this protocol, all patients, including those who discontinue protocol therapy early, will be followed 
for response until progression, and for survival every 6 months for 2 years, for a maximum of four 
years from the date of registration to assess for MDS/AML and overall survival. All patients must also 
be followed through completion of all protocol therapy. 
k. For any patient diagnosed with MDS/AML while on study, a bone marrow aspirate/biopsy must be 
completed by a local hematologist. 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 methods are acceptable to GSK. 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.  
l. 
Post end of treatment visit (in-person, virtual, or televisit) will be conducted at 30 days (+/- 7 days) 
post last date of treatment, and follow-up exams will be conducted every 3 months for 1 year, and 
every 6 months for the remainder of the time for a maximum of 4 years from the date of registration.   
 
6.2.3 Biological Sample Collection for Correlative Studies 
Archival tumor tissue or fresh biopsy of recurrent or persistent tumor obtained via recent surgery 
will be used  for molecular profile, HRD, & other correlative studies. The patients will be 
requested to provide the results of any prior genetic testing they may have undergone within 6 
months of screening.  
 
Tumor samples will be evaluated by central testing to identify those with homologous-
recombination deficiency (using myChoice test, Myriad Genetics). Homologous-recombination 
deficiency will be defined as the presence of a BRCA deleterious mutation, a score of at least 
42 on the myChoice test or other relevant genetic analyses.  
 


Version 5.0 (30-Aug-2022) 
OU-SCC-PI-4G 
23 
 
For patients with recurrence or tumor progression after treatment with niraparib, if a tumor 
resection or a new biopsy is performed for clinical standard of care, then we will request that the 
tissue be sent for repeat genetic testing with myChoice test.  
The genetic testing results will be used for comparison of treatment response to HRD status [via 
LOH (Loss of Heterozygosity), TAI (telomeric-allelic imbalances), and LST (large-scale state 
transitions) results] and in a multivariant analysis to discover any genetic profiles influencing 
treatment response. 
For additional details, see lab manual.  
 
6.2.4 Follow up Parameter 
Follow-up is required as outlined in Table 4. In brief, patients will be seen every 28 days (prior to 
each cycle of therapy) while receiving study treatment. MRI / CT scans to assess response will 
be performed every eight weeks for six months, and then every 12 weeks until progression. 
Patients will also be seen 30 days (+/- 7 days) after last study medication is issued. Required 
study procedures are based on the presence or absence of study treatment related toxicities. 
Additionally, birth control must continue for six months after discontinuation of niraparib.  
 
For participants who are thought to be lost to follow-up, at least three documented attempts, 
including one via certified mail, should be made to contact the participant before the participant 
is deemed lost to follow-up. 
 
A patient is considered off study therapy when the patient has progressed or died prior to 
completion of study therapy, a non-protocol drug or therapy (directed at the disease) is initiated 
or all study therapy is totally discontinued. Survival and progression data will continue to be 
collected for at least two years after the patient is off study. 
 
 STUDY MEDICATION 
 
7.1 Niraparib 
7.1.1 Formulation  
Niraparib ([3S]-3-[4-(7-(aminocarbonyl)-2H-indazol-2-yl) phenyl] piperidine [tosylate 
monohydrate salt]) is an orally available, potent, highly selective PARP1 and PARP2 inhibitor. 
The excipients for niraparib are lactose monohydrate and magnesium stearate. Niraparib will be 
supplied as 100-mg capsules. 
7.1.2 Storage 
Niraparib 100-mg capsules will be packed in high-density polyethylene bottles with child 
resistant closures that contain 72 or 93 capsules per bottle. Niraparib supplies must be stored at 
room temperature. Until dispensed or administered to the patients, the study treatment will be 
stored in a securely locked area, accessible to authorized personnel only. 
7.1.3 Administration 
Niraparib will be supplied as 100-mg capsules and will be administered orally once daily (QD) 
continuously starting on Cycle 1/Day 1. The daily dose to be administered each day will be 300 
mg as 3 × 100 mg capsules, unless specified otherwise based on Table 1 or dosage alteration 
following the safety review. Patients will be instructed to take their dose at the same time each 


Version 5.0 (30-Aug-2022) 
OU-SCC-PI-4G 
24 
 
day, preferably in the morning. Bedtime administration may be a potent method for managing 
nausea. Niraparib may be taken with or without food. Patients must swallow whole and not 
chew capsules.  
Niraparib capsules will be dispensed to patients on Cycle 1 Day 1, and on Day 1 of every cycle 
(28-day cycles) thereafter until the patient discontinues study treatment. On Day 1 of each 
cycle, a niraparib dose will be administered at the clinic upon completion of the safety 
assessment and drug accountabilities. Patient has an option to administer medication at 
bedtime in the case of nausea post dose. To ensure no study medication is wasted, patients will 
be provided 1 cycle worth of drug at each dispensing and patients will be provided with a pill 
diary to keep track of their medication. Patients are to return unused medications to clinic site to 
be destroyed per institutional standard.  
If the patient missed a dose > 12 hours from the normal dosing time, skip the dose until the next 
regularly scheduled dosing time. If patient vomits post dose, skip the dose until the next 
regularly scheduled dosing time.  
7.1.4 Clinically Reported Adverse Reactions  
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. 
 
 
 EVALUATION CRITERIA 
8.1 Parameters of Outcome – RANO Criteria or Macdonald Criteria   
The primary measure of response will be by serial measures of the product of the two largest 
cross-sectional diameters using Response Assessment in Neuro-Oncology (RANO), which is 
summarized in Appendix B [31]. The older Macdonald Criteria is available in Appendix C [32]. 
Time interval to progression will be measured from registration until deterioration is documented 
by the investigator using these guides. The patient should consistently be followed with the 
same diagnostic imaging study (CT or MRI). NOTE: CT option ONLY for patients unable to 
undergo MR imaging because of non-compatible devices. 
 
8.1.1 Definition of Measurable Lesions  
Measurable disease is defined as at least one lesion that can be accurately measured in at least 
one dimension (longest dimension to be recorded). Each lesion must be ≥ 10 mm x 10 mm 


Version 5.0 (30-Aug-2022) 
OU-SCC-PI-4G 
25 
 
(perpendicular measurements) on 5 mm slices on MRI when measured by conventional 
techniques, including MRI and CT.  
 
8.1.2 Baseline documentation of “Target” and “Non-Target” lesions  
All measurable lesions should be identified as target lesions and will be recorded and measured 
at baseline. Target lesions should be selected on the basis of their size (see above) and their 
suitability for accurate repetitive measurements by one consistent method of assessment (either 
by imaging techniques or clinically). A sum of the products of the diameters will be reported for 
all target lesions at baseline.  
All other lesions should be identified as non-target lesions and should also be recorded at 
baseline. Measurements are not required and each of these lesions should be followed (the 
persistence of a non-target lesion), complete response (the disappearance of a non-target 
lesion) or progressive disease (the unequivocal progression of a non-target lesion).  
All baseline evaluations of disease status should be performed as close as possible to the start 
of treatment and never more than 4 weeks before the beginning of treatment.  
Measurement of the sum of the products of the diameters (RANO) for target lesion size is 
required for follow-up. Change in the sum of these dimensions affords some estimate of change 
in tumor size and hence therapeutic efficacy. All disease must be assessed using the same 
technique as baseline.  
 
8.1.3 Response Criteria 
Complete Response (CR): complete disappearance of the measurable enhancing lesion 
sustained for at least 4 weeks; no new lesions; and no corticosteroids. 
Partial Response (PR):  ≥ 50% decrease compared with baseline in the sum of products of 
perpendicular diameters of the measurable enhancing lesion sustained for at least 4 weeks; no 
new lesions; and stable or reduced corticosteroid dose. 
Stable Disease (SD): does not qualify for complete response, partial response, or progression 
and is receiving stable or decreasing doses of steroids. This will not require a confirmatory scan. 
Progression (P): Defined by any of the following: ≥ 25% increase in sum of the products of 
perpendicular diameters of enhancing lesions provided that the patient has not had his/her dose 
of steroids decreased since the last evaluation period; and any new lesions. This will not require 
a confirmatory scan. A concomitant decrease in steroid dose will rule out a progression 
designation during the initial 12 weeks after completion of RT. 
If true progression is determined by subsequent imaging, then the date of progression returns to 
the earlier date with increasing mass. 
 
8.1.4 RANO Response Criteria 
Efficacy determinations using RANO response criteria (Appendix B) will be obtained. 
Criteria for Response Assessment Incorporating MRI and Clinical Factors 
 
Complete Response: Requires all of the following: 
• 
Complete disappearance of all enhancing measurable and non-measurable 
disease sustained for at least 4 weeks. 
• 
No new lesions. 


Version 5.0 (30-Aug-2022) 
OU-SCC-PI-4G 
26 
 
• 
Stable or improved non-enhancing (T2/FLAIR) lesions. 
• 
Patients must be off corticosteroids (or on physiologic replacement doses only). 
• 
Stable or improved clinically. 
Note: Patients with non-measurable disease only cannot have a complete response. The best 
response possible is stable disease. 
 
Partial Response: Requires all of the following: 
• 
Greater than or equal to 50% decrease compared to baseline in the sum of 
products of perpendicular diameters of all measurable enhancing lesions 
sustained for at least 4 weeks. 
• 
No progression of non-measurable disease. 
• 
No new lesions. 
• 
Stable or improved non-enhancing (T2/FLAIR) lesions on same or lower dose of 
corticosteroids compared to baseline scan. 
• 
The corticosteroid dose at the time of the scan evaluation should be no greater 
than the dose at time of baseline scan. 
• 
Stable or improved clinically. 
Note: Patients with non-measurable disease only cannot have a partial response. The best 
response possible is stable disease. 
 
Stable Disease: Requires all of the following: 
• 
Does not qualify for complete response, partial response, or progression. 
• 
Stable non-enhancing (T2/FLAIR) lesions on same or lower dose of 
corticosteroids compared to baseline scan. In the event that the corticosteroid 
dose was increased for new symptoms and signs without confirmation of disease 
progression on neuroimaging, and subsequent follow-up imaging shows that this 
increase in corticosteroids was required because of disease progression, the last 
scan considered to show stable disease will be the scan obtained when the 
corticosteroid dose was equivalent to the baseline dose. 
• 
Stable or improved clinically. 
 
Progression: Defined by any of the following: 
• 
Greater than > 25% increase in sum of the products of perpendicular diameters 
of enhancing lesions compared to the smallest tumor measurement obtained 
either at baseline (if no decrease) or best response, on stable or increasing 
doses of corticosteroids*. 
• 
Significant increase in T2/FLAIR non-enhancing lesion on stable or increasing 
doses of corticosteroids compared to baseline scan or best response following 
initiation of therapy*, not due to co-morbid events (e.g. radiation therapy, 
demyelination, ischemic injury, infection, seizures, post-operative changes, or 
other treatment effects). 
• 
Any new lesion. 


Version 5.0 (30-Aug-2022) 
OU-SCC-PI-4G 
27 
 
• 
Clear clinical deterioration not attributable to other causes apart from the tumor 
(e.g. seizures, medication side effects, complications of therapy, cerebrovascular 
events, infection, etc.) or changes in corticosteroid dose. 
• 
Failure to return for evaluation due to death or deteriorating condition. 
• 
Clear progression of non-measurable disease. 
*Stable doses of corticosteroids include patients not on corticosteroids 
 
8.1.5 Overall Survival is the observed length of life from the date of study 
entry to death or the date of last contact.  
 
8.1.6 Progression-Free Survival (PFS) is defined as the time in months from 
date of study entry to the first documented date of progression (based on 
RANO) or date of death, whichever comes first. For patients who did not 
die and did not have progression, the PFS is censored at the last 
documented tumor assessment.  .  
 
8.1.7 Special Considerations: If the patient was previously treated with 
bevacizumab or other anti-angiogenic medication, the MRI changes must 
be taken into consideration as the cessation of such drugs can artificially 
increase the contrast enhancement of the tumor and surrounding area 
without indicating tumor progression. These MRI’s will be specifically 
reviewed with the PI and radiology to determine if the changes are due to 
anti-angiogenic drug withdrawal or true tumor progression.  MRI perfusion 
scans are recommended to improve assessment of such lesions 
changes. In addition, a repeat MRI in 4 weeks (+/- 7 days) is allowed to 
determine the stability of the lesion and thereby determine if the changes 
are related to tumor progression or to medication changes.  During the 
time waiting for a new scan, the patient may continue to treat with 
niraparib at the same dose level. 
 
8.2 Subjective Parameters:  
The ECOG performance status is summarized in Appendix D. The specific symptoms, and side 
effects are graded according to the CTCAE v 5.0. 
 
 Safety Monitoring and Reporting Procedures 
The safety plan for patients in this study is based on clinical experience with niraparib in 
completed and ongoing studies. The anticipated important safety risks are outlined in sections 
1.4.3 and 5.4.  
 
Measures will be taken to ensure the safety of patients participating in this study, including the 
use of stringent inclusion and exclusion criteria and close monitoring of patients during the 
study. After initiation of study treatment, all nonserious adverse events will be reported until 30 
days after the last dose of study or until 90 days after cessation of study treatment for SAEs and 
AESIs (unless otherwise specified, see section 9.1.2). Guidelines for managing anticipated 


Version 5.0 (30-Aug-2022) 
OU-SCC-PI-4G 
28 
 
adverse events, including criteria for dosage modification and treatment interruption or 
discontinuation, are provided in section 5.4.   
Safety assessments will consist of monitoring and reporting adverse events and serious 
adverse events per protocol.  This includes all events of death and any study-specific issue of 
concern. 
 
9.1 Adverse Event Monitoring and Management 
The investigator is responsible for ensuring that all AEs and SAEs that are observed or reported 
during the study, are collected and reported to appropriate IRB(s), and GSK. 
 
9.1.1 Definitions (per 21 CFR 312.32(a)): 
Adverse event: “Any untoward medical occurrence associated with the use of a drug in 
humans, whether or not considered drug related.”  
This includes the following: 
• 
AEs not previously observed in the subject that emerge during the protocol-specified 
AE reporting period, including signs or symptoms associated with study treatment 
that were not present prior to the AE reporting period. 
• 
Complications that occur as a result of protocol-mandated interventions (e.g., 
invasive procedures such as tumor biopsy). 
• 
If applicable, AEs that occur prior to assignment of study treatment associated with 
medication washout, no treatment run-in, or other protocol-mandated intervention. 
• 
Preexisting medical conditions (other than the condition being studied) judged by the 
investigator to have worsened in severity or frequency or changed in character 
during the protocol-specified AE reporting period. 
• 
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. 
 
Life-threatening adverse event or life-threatening suspected adverse reaction: “An 
adverse event or suspected adverse reaction is considered “life threatening” if, in the view of 
either the investigator or sponsor, its occurrence places the patient or subject at immediate risk 
of death. It does not include an adverse event or suspected adverse reaction that, had it 
occurred in a more severe form, might have caused death.”  
 
Serious adverse event or serious suspected adverse reaction: “An adverse event or 
suspected adverse reaction is considered “serious” if, in the view of either the investigator or 
sponsor, it results in any of the following outcomes: 
• 
Death,  
• 
A life-threatening adverse event,  
• 
Inpatient hospitalization or prolongation of existing hospitalization,  
• 
A persistent or significant incapacity or substantial disruption of the ability to conduct 
normal life functions, or  


Version 5.0 (30-Aug-2022) 
OU-SCC-PI-4G 
29 
 
• 
A congenital anomaly/birth defect.  
Important medical events that may not result in death, be life-threatening, or require 
hospitalization may be considered serious when, based upon appropriate medical judgment, 
they may jeopardize the patient or subject and may require medical or surgical intervention to 
prevent one of the outcomes listed in this definition. Examples of such medical events include 
allergic bronchospasm requiring intensive treatment in an emergency room or at home, blood 
dyscrasias or convulsions that do not result in inpatient hospitalization, or the development of 
drug dependency or drug abuse.” 
 
Suspected adverse reaction: “Suspected adverse reaction means any adverse event for 
which there is a reasonable possibility that the drug caused the adverse event. “Reasonable 
possibility” means there is evidence to suggest a causal relationship between the drug and the 
adverse event. Suspected adverse reaction implies a lesser degree of certainty about causality 
than adverse reaction, which means any adverse event caused by a drug.” 
 
Unexpected adverse event or unexpected suspected adverse reaction: “An adverse event 
or suspected adverse reaction is considered “unexpected” if it is not listed in the investigator 
brochure or is not listed at the specificity or severity that has been observed. For example, 
under this definition, hepatic necrosis would be unexpected (by virtue of greater severity) if the 
investigator brochure referred only to elevated hepatic enzymes or hepatitis. Similarly, cerebral 
thromboembolism and cerebral vasculitis would be unexpected (by virtue of greater specificity) if 
the investigator brochure listed only cerebral vascular accidents. “Unexpected,” as used in this 
definition, also refers to adverse events or suspected adverse reactions that are mentioned in 
the investigator brochure as occurring with a class of drugs or as anticipated from the 
pharmacological properties of the drug, but are not specifically mentioned as occurring with the 
particular drug under investigation.” 
The descriptions and grading scales found in the revised NCI Common Terminology Criteria for 
Adverse Events (CTCAE) version 5.0 will be utilized for AE reporting. All appropriate treatment 
areas should have access to a copy of the CTCAE version 5.0. A copy of the CTCAE version 
5.0 can be downloaded from the CTEP web site (http://ctep.cancer.gov). 
 
Events or Outcomes Not Qualifying as Serious Adverse Events 
The following are not considered SAEs and therefore do not need to be reported as such: 
• 
Pre-planned or elective hospitalization including social and/ or convenience 
situations  
• 
Hospital visits of less than 24 hours duration (eg, patient presents to the emergency 
room, but is not admitted to a ward)  
• 
Overdose of study treatment or concomitant medication unless the event meets SAE 
criteria (eg, hospitalization). See bullet 5, definition of an Adverse Event.  
• 
Events of progression of the patient’s underlying cancer as well as events clearly 
related to progression of the patient’s cancer (signs and symptoms of progression) 
should not be reported as a serious adverse event unless the outcome is fatal within 
the safety reporting period. If the event has a fatal outcome within the safety 


Version 5.0 (30-Aug-2022) 
OU-SCC-PI-4G 
30 
 
reporting period, then the event of Progression of Disease must be recorded as an 
AE and as a SAE with CTCAE Grade 5 (fatal outcome) indicated. 
9.1.2 Definition of an Adverse Events of Special Interest 
AESIs (serious or non-serious) are defined as AEs of scientific and medical concern specific to 
a product or program, for which ongoing monitoring and rapid communication can be 
appropriate. Such an event might warrant further investigation in order to characterize and 
understand it. Depending on the nature of the event, rapid communication by the Sponsor to 
other parties (eg, regulators) might also be warranted. 
 Adverse Events of Special Interest for Niraparib 
AESIs for this trial are defined as:  
• 
Myelodysplastic Syndromes (MDS) 
• 
Acute Myeloid Leukemia (AML) 
• 
Secondary cancers defined as any new cancers that are identified after the initiation of 
protocol therapy. Exceptions include: 
• 
adequately treated nonmelanoma skin cancer, curatively treated in-situ cancer of 
the cervix, ductal carcinoma in-situ (DCIS) of the breast, Stage I Grade 1 
endometrial carcinoma 
• 
Other solid tumors and lymphomas (without bone marrow involvement) 
diagnosed ≥5 years prior to study participation and treated with no evidence of 
disease recurrence and for whom no more than 1 line of chemotherapy was 
applied. 
 
AESIs meeting the definition of an SAE must be reported within 24 hours of awareness of the 
event to the Sponsor Institution and to GSK regardless of causality assessment to study drug 
and regardless of the timeframe since the last dose. A targeted follow-up questionnaire (TFUQ) 
is available for MDS/AML (see section 9.1.5). 
 
9.1.3 Pregnancy 
The Sponsor Institution has the responsibility to monitor the outcome of all pregnancies reported 
during the Investigator Sponsored Trial. 
The Sponsor Institution 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 a  Pregnancy Notification Form (Appendix E) within 24 
hours of becoming aware of the pregnancy. Pregnancy is not an AE, and therefore does not 
need to be reported as an AE unless there is a suspicion that the study drug may have 
interfered with the effectiveness of a contraceptive medication.  
An elective abortion without complications should not be regarded as an AE, however, it should 
be reported as the outcome to the pregnancy on the Pregnancy Follow-Up Form (Appendix F). 
Therapeutic abortions should be reported as a treatment procedure; the reason for the 
therapeutic abortion should be reported on the Pregnancy Follow-Up 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 Follow-Up Form, 
reported as an SAE on the SAE Report Form (e.g., maternal serious complications, therapeutic 


Version 5.0 (30-Aug-2022) 
OU-SCC-PI-4G 
31 
 
abortion, ectopic pregnancy, stillbirth, neonatal death, congenital anomaly, birth defect) and 
reported to the Sponsor Institution and GSK within 24 hours. SAE Report form is listed in 
Appendix G. Hospitalization for normal delivery of a healthy newborn should not be considered 
an SAE.  
The Pregnancy Notification form, the Pregnancy Follow-Up Form, and any related SAE forms 
must be reported to the Sponsor as outlined for SAEs. 
 
9.1.4 Adverse Event Reporting Period 
The study period during which all AEs and SAEs must be reported begins after informed 
consent is obtained and initiation of study treatment and ends 30 days following the last 
administration of study treatment or study discontinuation/termination. After this period, 
investigators should only report SAEs that are attributed to study treatment and serious AESIs. 
 
9.1.5 Documenting Adverse Events 
All AE information must be documented on the case report forms. Additional follow-up 
information (e.g., test results, autopsy, and discharge summary) may be obtained to supplement 
AE reports.. A copy of all initial and follow-up SAE reports will be included with the patient’s 
study files. 
 Specific Instructions for Recording Adverse Events 
Investigators should use correct medical terminology/concepts when reporting AEs or SAEs.  
Avoid colloquialisms and abbreviations. 
 
Diagnosis versus Signs and Symptoms: If known at the time of reporting, a diagnosis should 
be reported rather than individual signs and symptoms (e.g., record only liver failure or hepatitis 
rather than jaundice, asterixis, and elevated transaminases).  However, if a constellation of 
signs and/or symptoms cannot be medically characterized as a single diagnosis or syndrome at 
the time of reporting, it is acceptable to report the information that is currently available.  If a 
diagnosis is subsequently established, it should be reported as follow-up information. 
 
Deaths: All deaths that occur during the protocol-specified AE reporting period, regardless of 
attribution, will be reported to the appropriate parties.  When recording a death, the event or 
condition that caused or contributed to the fatal outcome should be reported as the single 
medical concept.  If the cause of death is unknown and cannot be ascertained at the time of 
reporting, report “Unexplained Death”. 
 
Preexisting Medical Conditions: A preexisting medical condition is one that is present at the 
start of the study.  Such conditions should be reported as medical and surgical history.  A 
preexisting medical condition should be re-assessed throughout the trial and reported as an AE 
or SAE only if the frequency, severity, or character of the condition worsens during the study.  
When reporting such events, it is important to convey the concept that the preexisting condition 
has changed by including applicable descriptors (e.g., “more frequent headaches”). 
 
Hospitalizations for Medical or Surgical Procedures: Any AE that results in hospitalization or 
prolonged hospitalization should be documented and reported as an SAE.  If a subject is 


Version 5.0 (30-Aug-2022) 
OU-SCC-PI-4G 
32 
 
hospitalized to undergo a medical or surgical procedure as a result of an AE, the event 
responsible for the procedure, not the procedure itself, should be reported as the SAE.  For 
example, if a subject is hospitalized to undergo coronary bypass surgery, record the heart 
condition that necessitated the bypass as the SAE. 
Hospitalizations for the following reasons do not require reporting: 
• 
Hospitalization or prolonged hospitalization for diagnostic or elective surgical procedures 
for preexisting conditions 
• 
Hospitalization or prolonged hospitalization required to allow efficacy measurement for 
the study or 
• 
Hospitalization or prolonged hospitalization for scheduled therapy of the target disease 
of the study 
 
9.1.6 Causality Assessment of Adverse Events 
The relationship between an AE and the study drug will be determined by the Investigator on 
the basis of his or her clinical judgment and the following definitions. 
An AE will be considered associated with the use of study drug if there is a reasonable 
possibility that the AE may have been caused by the study drug.  
The Investigator must provide a causality assessment regarding the relationship of the event 
with the study drug and/or study procedure for all AEs.   
 
One of the following categories should be selected based on medical judgment, considering all 
contributing factors: 
• 
Related: A causal relationship between the medicinal product (and/or study procedures) 
and AE is a reasonable possibility. For example, the occurrence of the AE cannot be 
explained by other causative factors. The AE, however, can be explained by 
pharmacological effect of the medicinal product such as a similar event having been 
reported previously, alteration of the dose effect, or the timing or seriousness of the AE, 
etc. Positive rechallenge/dechallenge is supportive.  
• 
Not Related: A causal relationship between the medicinal product (and/or study 
procedures) and AE is not a reasonable possibility: there is no temporal relationship 
between the medicinal product and event, or an alternative etiology is more reasonable. 
 
In addition, the following definitions may be applied to those AEs that are considered definitely, 
probably, and possibly related to the use of the study drug: 
Definitely Related: An AE that follows a temporal sequence from administration of the 
study drug; follows a known response pattern to the study drug; improves after stopping the 
study drug (positive dechallenge) and reappears after repeat exposure (positive 
rechallenge); and cannot be reasonably explained by known characteristics of the patient's 
clinical state or by other therapies 
Probably Related: An AE that follows a reasonable temporal sequence from administration 
of the study drug; follows a known response pattern to the study drug; improves after 
dechallenge; and cannot be reasonably explained by the known characteristics of the 
patient's clinical state or by other therapies. 


Version 5.0 (30-Aug-2022) 
OU-SCC-PI-4G 
33 
 
Possibly Related: An AE that follows a reasonable temporal sequence from administration 
of the study drug and follows a known response pattern to the study drug but could have 
been produced by the patient's clinical state or by other therapies An AE may be considered 
not associated with the use of study drug if there is not a reasonable possibility that the AE 
may have been caused by the study drug. This definition applies to those AEs that are 
considered unlikely or not related to the use of the study drug: 
Unlikely to be Related: An AE assessed as unlikely to be related to study drug is defined 
as an AE for which sufficient information exists to indicate a high improbability that the event 
is related to the study drug. 
 
If the AE falls under any of the above four categories, it will be listed as “Related to 
the drug” on the CRFs. 
 
Not Related: An AE assessed as not related to study drug is defined as an AE for which 
sufficient information exists to indicate that the etiology is unrelated to the study drug.  
Two or more of the following variables apply: 
• 
The AE does not follow a reasonable temporal sequence after administration of the 
study drug. 
• 
The AE is readily explained by the patient’s clinical state or other therapies. 
• 
Negative dechallenge—the AE does not abate upon dose reduction or cessation of 
therapy (assuming that it is reasonable to expect abatement of the AE within the 
observed interval). 
 
If the AE falls under the above category, it will be listed as “Not related to the drug” 
on the CRFs. 
 
9.1.7 Severity Assessment of Adverse Events 
Severity of AEs will be graded according to the CTCAE Version 5.0. 
Adverse events not included in the CTCAE, Version 5.0 must be graded as follows: Mild, 
Moderate, Severe, Life-threatening, and Fatal according to the following definitions: 
• 
Mild: The AE is noticeable to the patient but does not interfere with routine activity. 
• 
Moderate: The AE interferes with routine activity but responds to symptomatic therapy or 
rest. 
• 
Severe: The AE significantly limits the patient's ability to perform routine activities 
despite symptomatic therapy. 
• 
Life-threatening: The AE places the patient at risk of death at the time of the event. 
• 
Fatal: The AE results in the death of the patient. 
 
9.1.8 SAE Reporting 
The Investigator must report all SAEs, and all follow up information to the Sponsor and GSK on 
the GSK SAE Report Form or MedWatch 3500A form within 24 hours of becoming aware of the 
initial event or follow-up information. SAEs must be entered on the study REDCap database 
within 24 hours of becoming aware of the initial event or follow-up information, with the 
MedWatch 3500A form.  


Version 5.0 (30-Aug-2022) 
OU-SCC-PI-4G 
34 
 
The Investigator must provide a causality assessment and must sign and date all SAE Report 
Forms.   
If supporting documentation is included in the SAE submission to GSK (e.g., hospital reports, 
consultant reports, death certificates, autopsy reports, etc.), please redact any patient identifiers 
(including Medical Record number).  
 
GSK SAE, Serious AESI, Pregnancy Reporting Information 
GSK Email: OAX37649@gsk.com  
and 
Sponsor Notification: Study REDCap database  
 
Suspected Unexpected Serious Adverse Reactions (SUSARs)  
Per regulatory requirements, if an event is assessed by the Sponsor Institution as a Serious 
Unexpected Adverse Reaction (SUSAR), it is the responsibility of the Sponsor Institution to 
submit the SUSAR to Regulatory Authorities according to applicable regulations. GSK should 
receive a copy of the submission documents.  
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).  
 
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 investigator or qualified designee to GSK at 
gsk-rd.complaints@gsk.com  within 1 working day of first becoming aware of the possible 
defect.  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. 
 
Reporting to Sponsor 
All SAEs and UPs (unanticipated problems) must be reported to the Sponsor via the the 
REDCap database within 24 hours of becoming aware of the initial event or follow-up 
information for Sponsor reporting to Regulatory agencies.  
 
9.2 MedWatch 3500A Reporting Guidelines 
In addition to completing appropriate patient demographic and suspect medication information, 
the report should include the following information within the Event Description (section 5) of the 
MedWatch 3500A form: 
• 
Treatment regimen 


Version 5.0 (30-Aug-2022) 
OU-SCC-PI-4G 
35 
 
• 
Protocol description (and number, if assigned) 
• 
Description of event, severity, treatment, and outcome if known 
• 
Supportive laboratory results and diagnostics 
• 
Investigator’s assessment of the relationship of the adverse event to each investigational 
product and suspect medication 
MedWatch 3500A (Mandatory Reporting) form is available at 
http://www.fda.gov/medwatch/getforms.html  
 
Follow-up Information:  
Additional information may be added to a previously submitted report by any of the following 
methods: 
• 
Adding to the original MedWatch 3500A report and submitting it as follow-up 
• 
Adding supplemental summary information and submitting it as follow-up with the 
original MedWatch 3500A form  
• 
Summarizing new information and faxing it with a cover letter including patient identifiers 
(i.e., D.O.B. initial, patient number), protocol description and number, if assigned, brief 
adverse event description, and notation that additional or follow-up information is being 
submitted (The patient identifiers are important so that the new information is added to 
the correct initial report) 
 
9.3 Study Monitoring 
All aspects of the study will be carefully monitored at periodic intervals throughout the study per 
FDA/ICH “Guidance for Industry – E6 Good Clinical Practice: Consolidated Guidance” dated 
April 1996. All Case Report Forms (CRFs) will be up to 100% source verified against 
corresponding source documentation (e.g., office and clinical laboratory records) for each 
patient. The monitoring visits provide the PI with the opportunity to evaluate the progress of the 
study, to verify appropriate consent form procedures, review drug accountability and to verify 
the accuracy and completeness of CRFs, to resolve any inconsistencies in the study records 
and to assure that all protocol requirements, applicable FDA regulations, other requirements, 
and Investigator’s obligations are being fulfilled. 
Furthermore, this study will fall under the purview of the Sponsor’s study-specific monitoring 
plan. 
9.4 Data Disclosure and Patient Confidentiality 
Patient medical information obtained as a result of this study is considered confidential. 
Disclosure to third parties other than those noted below is prohibited. All reports and 
communications relating to patients in this study will identify each patient only by their initials 
and number. Medical information resulting from a patient’s participation in this study may be 
given to the patient’s personal physician or to the appropriate medical personnel responsible for 
the patient’s welfare. Data generated as a result of this study are to be available for inspection 
on request by FDA or other government regulatory agency inspectors, the clinical trial office 
auditors and monitors, University of Oklahoma Office of Compliance, and the Institutional 
Review Board (IRB)). 
All laboratory specimens, evaluation forms, reports, and other records that leave the site will be 
identified by a coded number to maintain patient confidentiality. All study records will be kept in 


Version 5.0 (30-Aug-2022) 
OU-SCC-PI-4G 
36 
 
a locked file cabinet or other secured area. All computer entry and networking programs will be 
identifiable only by coded numbers. Patient personal medical information may be reviewed by 
representatives of the Sponsor, of the IRB, or of regulatory authorities in the course of 
monitoring the progress of the clinical trial. Every reasonable effort will be made to maintain 
such information as confidential. 
 
 STATISTICAL ANALYSIS PLAN  
Consideration for sample size 
This phase II study consists of a safety lead-in and a dose-expansion phase. In the safety 
lead-in phase, three or six patients will be enrolled depending on the safety profile. See 
Section 6.1 for more details. A total of 45 evaluable patients (including those from the safety 
lead-in phase), evenly distributed among 3 gliomas including GBM, Astrocytoma, and 
Oligodendroglioma, will be enrolled into dose-expansion phase. Conservatively allowing for 
up to 10% dropout, we will enroll up to 48 patients for an evaluable 45 patients.   In the 
sample size calculation, the DCR (disease control rate) for the historical control and for 
Niraparib are assumed to be 31% and 52%, respectively.  A sample size of 45 evaluable 
patients will provide 80% power to show statistical significance for a two-sided .05 level Z-
test.  
 
10.1 
Analysis Populations  
The safety lead-in and dose-expansion phases will be statistically analyzed separately.  The 
safety lead-in phase analysis population will include all patients who have received at least 
one dose of niraparib. 
 
The analysis populations in the dose-expansion phase are defined as below. 
• 
Safety population: All patients who receive at least one dose of niraparib will be 
included in the analyses of compliance and safety.   
• 
Biomarker population: For biomarker analysis, the biomarker population will 
comprise all patients who have sufficient baseline measurements. 
• 
Efficacy Evaluable population: For tumor response analysis, the evaluable population 
will comprise all patients who have sufficient baseline and on-study measurements of 
tumor response parameters. 
 
10.2 
Data Analysis  
10.2.1 Patient Disposition  
Patient disposition will be summarized and include the number dosed, the number in each 
patient population for analysis, the number who withdrew prior to completing the study and 
reason(s) for withdrawal.  
 
10.2.2 Demographic and Baseline Characteristics 
Patient demographic and characteristics at study entry will be summarized with frequency 
tables for categorical variables, and with descriptive statistics such as the mean, standard 
deviation, median, and range as appropriate, for quantitative variables. 
 


Version 5.0 (30-Aug-2022) 
OU-SCC-PI-4G 
37 
 
10.2.3 Medical History and Cancer History 
Medical history will be coded using the Medical Dictionary for Regulatory Activities 
(MedDRA) v20.1. The count and percentage of subjects under each history term, coded by 
system organ class (SOC) and preferred term (PT), will be summarized. 
Cancer history data will also be summarized, including the primary site of cancer, the stage 
and grade of cancer at study entry, time from initial diagnosis of cancer to Day 1 of the study 
in days, duration of metastatic disease in days (first dose date – date of diagnosis of 
metastatic disease + 1), the extent of metastatic disease, and the histology. 
 
10.2.4 Study Drug Administration and Compliance 
Study drug administration will be summarized in terms of the actual doses administered and 
the proportion of drug actually taken relative to the amount that should have been taken; 
these data will be summarized in frequency distributions by cycle and dose level.  The total 
number of cycles administered; the median (range) of cycles administered; dose 
modifications, dose delays, and dose omissions; and reasons for deviations from planned 
therapy will be summarized by dose level.   
 
10.2.5 Safety Analyses 
 
Adverse Events 
Adverse events will be tabulated using MedDRA v23.1. The severity of the AE will be 
graded by the Investigator using the NCI CTCAE, version 5.0. The frequency of patients 
experiencing a specific AE will be tabulated by dose level, cycle, system organ class, 
preferred term, seriousness, worst severity, timing of occurrence, outcome, and 
relationship to study drug.  In addition, the number and percentage of patients 
experiencing a specific AE will be tabulated similarly.   
 
Laboratory Abnormalities 
The severity of laboratory abnormalities will be graded using the NCI CTCAE, version 
5.0, whenever possible.  The frequency of patients experiencing a specific laboratory 
abnormality will be tabulated by dose level, cycle, worst severity, and timing of 
occurrence.  In addition, the number and percentage of patients experiencing a specific 
laboratory abnormality will be summarized similarly. 
 
Other Safety Assessments 
The results of vital sign measurements, body weight assessments, ECOG performance 
status determinations and physical examinations will be summarized by cycle and dose 
level, using appropriate descriptive statistics. 
 
10.2.6 Biomarkers 
Data of molecular profile from myChoice test will be collected. The tumor biomarkers from 
tumor biopsies, such as HRD, IDH1 /IDH2 mutation and PARP in tumor, will be summarized 
for each patient.  
 
10.2.7 Antitumor Evaluation 
The statistical analysis for the dose-expansion phase will be performed by the types of 
gliomas. The disease control rate (complete and partial response, and stable disease) will 


Version 5.0 (30-Aug-2022) 
OU-SCC-PI-4G 
38 
 
be summarized as the proportion (and 95% exact Clopper-Pearson CI) of patients with 
disease control. The duration of disease control (DDC) will be calculated as time from date 
of first response [complete response (CR), partial response (PR), pathological complete 
response (pCR), or stable disease (SD)] to the first date of non-response post treatment on 
the study (first documentation of disease progression or death, whichever comes first) 
Duration of disease control will be summarized using the Kaplan-Meier method. Median 
duration of disease control with 95% CI will be computed. Results will be presented in 
tabular and graphic form, as appropriate. The response rate will be compared between 
biomarker status using the chi-squared test and/or Fisher’s Exact Test, where applicable. 
   
Progression-Free Survival (PFS) is defined as the time in months from study entry to the first 
documented date of progression or date of death, whichever comes first. For patients who 
did not die and did not have progression, the PFS is censored at the last documented tumor 
assessment.  Survival curve for PFS will be generated using the Kaplan-Meier method.  
Median PFS with 95% CI will be computed. Six-month PFS rate is defined as the 
percentage of patients who are alive and progression-free at 6-month from the start of study 
treatment; with tumor response including CR (or pathological CR), PR and SD (estimated by 
the Kaplan-Meier method). PFS will be compared between biomarker status using the log-
rank test. 
 
Overall survival (OS) time is defined as the length of time from date of study entry to death 
or the date of last contact. Patients who are still alive at EOS are censored on the date they 
were last known to be alive.  An exploratory analysis to determine 6 months or 9 months OS 
rate will be estimated by the Kaplan-Meier method. Median OS with 95% CI will be 
computed. OS will be compared between biomarker status using the log-rank test. 
 
The raw data may be reviewed and evaluated by the PI, biostatistics team, and sponsor at 
any given point for the purposes of updating the study team, presentation at conferences, 
development of new protocols, grant applications, or other functions once discussed with the 
study management team at GSK.  
 
10.3 
Accrual and Study Duration   
This is a single arm, phase II, multi-center study. Forty-five evaluable patients will be enrolled at 
two medical centers including the Stephenson Cancer Center. Based on our prior experience 
with similar patient population, we anticipate enrollment of 20-25 patients in two years at both 
study sites.  
Up to six patients will be enrolled in the safety lead-in phase as outlined in Section 6.1. These 
patients will be included in the dose expansion phase total patient analysis in which a total of 45 
evaluable patients will be enrolled. Conservatively allowing for up to 10% dropout, we will enroll 
up to 48 patients for an evaluable 45 patients. It is anticipated that this study will require 
approximately 24-36 months of accrual assuming a uniform accrual rate of ~10 patients per 
year at each site. It is estimated that 12 months of post accrual follow-up will be necessary to 
observe the minimum number completed cycles. 
 


Version 5.0 (30-Aug-2022) 
OU-SCC-PI-4G 
39 
 
 DATA MANAGEMENT PLAN 
11.1 
Data Quality Assurance 
Stephenson Cancer Center (SCC) will be responsible for clinical monitoring of all data for this 
study.   
 
11.2 
Electronic Case Report Forms 
The Principal Investigator will develop electronic case report forms for study data entry. All study 
data will be stored in a 21 CFR 11 compliant database. Only Investigator and assigned research 
staff will have access to study data. The electronic case report forms will be available to the 
sponsor, IRB and regulatory authorities in event of an audit.   
 
11.3 
Data and Safety Monitoring Committee 
Safety oversight will be performed by Stephenson Cancer Center’s (SCC) internal Data and 
Safety Monitoring Committee (DSMC). The DSMC is composed of individuals with the 
appropriate expertise in adult and pediatric hematology and medical oncology, radiation 
oncology, translational and correlative science, pharmacy, nursing and biostatistics. The DSMC 
operates under the rules of an approved data safety monitoring plan which complies with the 
National Cancer Institute (NCI) guidelines published as Essential Elements of a Data and Safety 
Monitoring Plan for Clinical Trials Funded by NCI as of January 2005 and the “NIH Policy for 
Data and Safety Monitoring,” NIH Guide for Grants and Contracts, 
http://grants.nih.gov/grants/guide/notice-files/not98-084.html. 
The Data Safety Monitoring Committee is charged with oversight of participant safety, study 
conduct and the validity and integrity of data for clinical trials at SCC. While the focus of the 
DSMC is to monitor interventional investigator initiated trials (IITs) that are not subject to 
external monitoring, it has the authority to monitor any SCC protocol when potential concerns 
are identified. The DSMC also has the authority to suspend or close a study until the principal 
investigator addresses any issues that may cause harm or increase risks to subjects.  The 
DSMC reports all findings to the Institutional Review Board (IRB).  
Under the direction of the DSMC chair, a full board meeting is convened on a quarterly basis to 
review the accumulated safety data, accrual information, and additional information as stated in 
the DSMC plan. 
 
11.4 
DSMC Auditing 
In addition to monitoring, the DSMC oversees an internal auditing process to ensure subject 
safety and data quality. All cancer-related clinical trials active at the SCC are eligible for audit; 
however, priority is placed on those clinical trials that are not monitored or audited by an outside 
entity. If an external entity conducts an audit of a clinical trial at the SCC, then the findings of 
that audit are reported to the DSMC, either through the formal audit report provided by the 
external auditing entity, if available, or from the PI, who will report any findings communicated 
during the audit process.  
 
11.5 
Record Retention  
Investigator will retain all research documents and case report forms at study site per 
institutional standards.   


Version 5.0 (30-Aug-2022) 
OU-SCC-PI-4G 
40 
 
 
 PUBLICATION PLAN 
The study drugs to be used in this protocol will be supplied by GSK Inc. under a 
Collaborative Agreement (CTA) between GSK Inc. and the University Oklahoma 
Stephenson Cancer Center (OUSCC).  
 
The following obligations/guidelines apply to the use of the Agent in this study: 
 
1. Agent(s) may not be used outside the scope of this protocol, nor can Agent(s) be 
transferred or licensed to any party not participating in the clinical study. 
Collaborator(s) data for Agent(s) are confidential and proprietary to Collaborator(s) 
and shall be maintained as such by the investigators. The protocol documents for 
studies utilizing Agents contain confidential information and should not be shared or 
distributed without the permission of GSK Inc. the Funding Collaborator. If a copy of 
this protocol is requested by a patient or patient’s family member participating on the 
study, the individual should sign a confidentiality agreement.  
 
2. Clinical Trial Data and Results and Raw Data developed under a Collaborative 
Agreement will be made available exclusively to Collaborator(s), OUSCC and the 
FDA, as appropriate and unless additional disclosure is required by law or court 
order as described in the IP Option to Collaborator. Additionally, all Clinical Data and 
Results and Raw Data will be collected, used and disclosed consistent with all 
applicable federal statutes and regulations for the protection of human subjects, 
including, if applicable, the Standards for Privacy of Individually Identifiable Health 
Information set forth in 45 C.F.R. Part 164. 
 
3. Any data provided to the Collaborator(s) for this study must be in accordance with 
the guidelines and policies of the responsible Data Monitoring Committee (DMC), if 
there is a DMC for this clinical trial. 
 
4. Potential manuscripts may be submitted to Neuro-Oncology, J. Neuro-Oncology, or 
JCO for publication. Any manuscripts reporting the results of this clinical trial must be 
provided to GSK by the principal investigator for advisory review and comment prior 
to submission for publication. Collaborator(s) will have 30 days from the date of 
receipt for review. Collaborator shall have the right to request that publication be 
delayed for up to an additional 30 days in order to ensure that Collaborator's 
confidential and proprietary data, in addition to the Collaborator(s)'s intellectual 
property rights, are protected. Copies of abstracts must be provided to GSK 
Collaborator(s) for courtesy review as soon as possible and preferably at least three 
(3) days prior to submission, but in any case, prior to presentation at the meeting or 
publication in the proceedings. Press releases and other media presentations must 
also be forwarded to GSK prior to release.  
 


Version 5.0 (30-Aug-2022) 
OU-SCC-PI-4G 
41 
 
No publication, manuscript or other form of public disclosure shall contain any of the 
Collaborator's confidential/proprietary information. 
 
 ETHICAL AND REGULATORY CONSIDERATIONS 
Before initiation of the study, the Investigators must provide the Sponsor with a completed Form 
FDA 1572. Study medication may be administered only under the supervision of the 
Investigators listed on this form. Curriculum vitae must be provided to the Sponsor for the site 
Principal Investigator and made available upon request for the sub-Investigators. 
 
13.1 
Ethical Conduct of the Study 
The study will be conducted in full conformance with the ICH E6 guideline for Good Clinical 
Practice and the principles of the Declaration of Helsinki in addition to the requirements of the 
ICH E2A guidelines. This study will also comply with U.S. FDA regulations in addition to local, 
state, and federal laws. 
 
13.2 
Informed Consent 
The informed consent document will be in compliance with ICH GCP, local regulatory 
requirements, and legal requirements. The informed consent document used in this study, and 
any changes made during the course of the study, will be prospectively approved by the IRB. 
The investigator must ensure that each study patient is fully informed about the nature and 
objectives of the study and possible risks associated with participation. The investigator, or a 
person designated by the investigator, will obtain written informed consent from each patient 
before any study-specific activity is performed. The study site will retain the original of each 
patient’s signed consent document. A signed copy of the informed consent document must be 
provided to the subject or the subject's legally authorized representative.  If applicable, it will be 
provided in a certified translation of the local language. 
 
13.3 
Institutional Review Board or Ethics Committee 
This protocol, the informed consent document, and relevant supporting information must be 
submitted to the IRB for review and must be approved before the study is initiated.  The study 
will be conducted in accordance with FDA and IRB requirements. 
The Principal Investigator is responsible for keeping the IRB apprised of the progress of the 
study and of any changes made to the protocol as deemed appropriate, but in any case, the IRB 
must be updated at least once a year.  The Principal Investigator must also keep the IRB 
informed of any significant AEs. 
Investigators are required to promptly notify their respective IRB of all adverse drug reactions 
that are both serious and unexpected.  This generally refers to SAEs that are not already 
identified in the Investigator’s Brochure and that are considered possibly or probably related to 
the molecule or study drug by the investigator.  Some IRBs may have other specific AE 
requirements to which investigators are expected to adhere. 
 
13.4 
Protocol Violations/Deviations 
The Investigator will conduct the study in compliance with the protocol. Modifications to the 
protocol will not be made without agreement of the Sponsor. Changes to the protocol will 


Version 5.0 (30-Aug-2022) 
OU-SCC-PI-4G 
42 
 
require written IRB approval prior to implementation, except when the modification is needed to 
eliminate an immediate hazard(s) to patients.  
When immediate deviation from the protocol is required to eliminate an immediate hazard to 
patients, the Investigator will contact the Sponsor or its designee if circumstances permit, to 
discuss the planned course of action. Any departures from the protocol must be fully 
documented as a protocol deviation. 
 REFERENCES 
1. 
Herceg, Z. and Z.Q. Wang, Functions of poly(ADP-ribose) polymerase (PARP) in DNA repair, 
genomic integrity and cell death. Mutat Res, 2001. 477(1-2): p. 97-110. 
2. 
Leonetti, C., et al., Targeted therapy for brain tumours: role of PARP inhibitors. Curr Cancer Drug 
Targets, 2012. 12(3): p. 218-36. 
3. 
Jones, P., et al., Discovery of 2-{4-[(3S)-piperidin-3-yl]phenyl}-2H-indazole-7-carboxamide (MK-
4827): a novel oral poly(ADP-ribose)polymerase (PARP) inhibitor efficacious in BRCA-1 and -2 
mutant tumors. J Med Chem, 2009. 52(22): p. 7170-85. 
4. 
Murai, J., et al., Trapping of PARP1 and PARP2 by Clinical PARP Inhibitors. Cancer Res, 2012. 
72(21): p. 5588-99. 
5. 
Mirza, M.R., et al., Niraparib Maintenance Therapy in Platinum-Sensitive, Recurrent Ovarian 
Cancer. N Engl J Med, 2016. 375(22): p. 2154-2164. 
6. 
Mikule, K., Wilcoxen, K., The PARP inhibitor, niraparib, crosses the blood brain barrier in rodents 
and is efficacious in a BRCA2-mutant intracranial tumor model. Molecular Cancer Therapeutics, 
2015. 14(12 Suppl 2): p. Abstract B168. 
7. 
Chornenkyy, Y., et al., Poly-ADP-Ribose Polymerase as a Therapeutic Target in Pediatric Diffuse 
Intrinsic Pontine Glioma and Pediatric High-Grade Astrocytoma. Mol Cancer Ther, 2015. 14(11): 
p. 2560-8. 
8. 
Davis, M.E., Glioblastoma: Overview of Disease and Treatment. Clin J Oncol Nurs, 2016. 20(5): p. 
S2-8. 
9. 
Stupp, R., et al., Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma. N 
Engl J Med, 2005. 352(10): p. 987-96. 
10. 
Stupp, R., et al., Effects of radiotherapy with concomitant and adjuvant temozolomide versus 
radiotherapy alone on survival in glioblastoma in a randomised phase III study: 5-year analysis of 
the EORTC-NCIC trial. Lancet Oncol, 2009. 10(5): p. 459-66. 
11. 
Siegel, R.L., K.D. Miller, and A. Jemal, Cancer statistics, 2016. CA Cancer J Clin, 2016. 66(1): p. 7-
30. 
12. 
Rahman, R., et al., Retrospective study of carmustine or lomustine with bevacizumab in recurrent 
glioblastoma patients who have failed prior bevacizumab. Neuro Oncol, 2014. 16(11): p. 1523-9. 
13. 
Ossovskaya, V., et al., Upregulation of Poly (ADP-Ribose) Polymerase-1 (PARP1) in Triple-
Negative Breast Cancer and Other Primary Human Tumor Types. Genes Cancer, 2010. 1(8): p. 
812-21. 
14. 
Galia, A., et al., PARP-1 protein expression in glioblastoma multiforme. Eur J Histochem, 2012. 
56(1): p. e9. 
15. 
Barazzuol, L., et al., Evaluation of poly (ADP-ribose) polymerase inhibitor ABT-888 combined with 
radiotherapy and temozolomide in glioblastoma. Radiat Oncol, 2013. 8: p. 65. 
16. 
Karpel-Massler, G., et al., PARP inhibition restores extrinsic apoptotic sensitivity in glioblastoma. 
PLoS One, 2014. 9(12): p. e114583. 
17. 
Jones, P., et al., Niraparib: A Poly(ADP-ribose) Polymerase (PARP) Inhibitor for the Treatment of 
Tumors with Defective Homologous Recombination. J Med Chem, 2015. 58(8): p. 3302-14. 


Version 5.0 (30-Aug-2022) 
OU-SCC-PI-4G 
43 
 
18. 
Bryant, H.E., et al., Specific killing of BRCA2-deficient tumours with inhibitors of poly(ADP-ribose) 
polymerase. Nature, 2005. 434(7035): p. 913-7. 
19. 
Mueller, S., et al., Poly (ADP-Ribose) polymerase inhibitor MK-4827 together with radiation as a 
novel therapy for metastatic neuroblastoma. Anticancer Res, 2013. 33(3): p. 755-62. 
20. 
Bridges, K.A., et al., Niraparib (MK-4827), a novel poly(ADP-Ribose) polymerase inhibitor, 
radiosensitizes human lung and breast cancer cells. Oncotarget, 2014. 5(13): p. 5076-86. 
21. 
Sulkowski, P.L., et al., 2-Hydroxyglutarate produced by neomorphic IDH mutations suppresses 
homologous recombination and induces PARP inhibitor sensitivity. Sci Transl Med, 2017. 9(375). 
22. 
Sandhu, S.K., et al., The poly(ADP-ribose) polymerase inhibitor niraparib (MK4827) in BRCA 
mutation carriers and patients with sporadic cancer: a phase 1 dose-escalation trial. Lancet 
Oncol, 2013. 14(9): p. 882-92. 
23. 
Liu, J.F., P.A. Konstantinopoulos, and U.A. Matulonis, PARP inhibitors in ovarian cancer: current 
status and future promise. Gynecol Oncol, 2014. 133(2): p. 362-9. 
24. 
Kurzrock, R., Galanis, E., Johnson, D.R.; et al.;, A phase I study of niraparib in combination with 
temozolomide (TMZ) in patients with advanced cancer. J Clin Oncol 2014. 32(suppl): p. Abstract 
2092, 2014 ASCO Annual Meeting  
25. 
Drugs associated with QT prolongation and TdP. Available at US Pharmacist web site: 
http://www.uspharmacist.com/content/d/featured_articles/c/10396/. Accessed 11 Aug 2015. 
26. 
Konstantinopoulos, P.A., et al., Single-Arm Phases 1 and 2 Trial of Niraparib in Combination With 
Pembrolizumab in Patients With Recurrent Platinum-Resistant Ovarian Carcinoma. JAMA Oncol, 
2019. 5(8): p. 1141-1149. 
27. 
Vinayak, S., et al., Open-Label Clinical Trial of Niraparib Combined With Pembrolizumab for 
Treatment of Advanced or Metastatic Triple-Negative Breast Cancer. JAMA Oncol, 2019. 5(8): p. 
1132-1140. 
28. 
Chalhoub, N. and S.J. Baker, PTEN and the PI3-kinase pathway in cancer. Annu Rev Pathol, 2009. 
4: p. 127-50. 
29. 
Mendes-Pereira, A.M., et al., Synthetic lethal targeting of PTEN mutant cells with PARP 
inhibitors. EMBO Mol Med, 2009. 1(6-7): p. 315-22. 
30. 
McEllin, B., et al., PTEN loss compromises homologous recombination repair in astrocytes: 
implications for glioblastoma therapy with temozolomide or poly(ADP-ribose) polymerase 
inhibitors. Cancer Res, 2010. 70(13): p. 5457-64. 
31. 
Quant, E.C. and P.Y. Wen, Response assessment in neuro-oncology. Curr Oncol Rep, 2011. 13(1): 
p. 50-6. 
32. 
Macdonald, D.R., et al., Response criteria for phase II studies of supratentorial malignant glioma. 
J Clin Oncol, 1990. 8(7): p. 1277-80. 
 
 
 


Version 5.0 (30-Aug-2022) 
OU-SCC-PI-4G 
44 
 
 APPENDIX 
 
Appendix A. Substrates for CYP1A2  
 
Data from https://www.fda.gov/drugs/ 
 
Sensitive substrates 
Moderate sensitive substrates 
CYP1A2 alosetron, caffeine, duloxetine, 
melatonin, ramelteon, tasimelteon 
clozapine, pirfenidone, ramosetron, 
theophylline 
 
Additional substrates for CYP1A2: Data from https://drug-interactions.medicine.iu.edu 
 
Acetaminophen, amitriptyline, clomipramine, cyclobenzaprine, doxepin, duloxetine, estradiol, 
fluvoxamine, haloperidol, imipramine n-deme, mexiletine, nabumetone, napqi, naproxen, 
olanzapine, ondansetron, phenacetin, propranolol, riluzole, ropivacaine, rcaparib, tacrine, 
tizanidine, triamterene, varpamil, warfarin, zileuton, zolmitriptan. 
  
 
 


Version 5.0 (30-Aug-2022) 
OU-SCC-PI-4G 
45 
 
Appendix B. Summary of RANO Response Criteria [31] 
 
Criterion 
 
CR 
PR 
SD  
PD# 
 
T1-Gd + 
None 
≥ 50%↓ 
< 50%↓ - < 
25%↑ 
≥ 25% ↑* 
T2/FLAIR 
Stable or ↓ 
Stable or ↓ 
Stable or ↓ 
↑* 
New Lesion 
None 
None 
None 
Present* 
 
Corticosteroids 
None 
Stable or ↓ 
Stable or ↓ 
NA** 
 
Clinical Status 
Stable or ↑ 
Stable or ↑ 
Stable or ↑ 
↓* 
Requirement 
for 
response 
All 
all 
All 
Any* 
 
 
Abbreviations: RANO, Response Assessment in Neuro-Oncology; CR=complete response; 
PR=partial response; SD=stable disease; PD=progressive disease; FLAIR, fluid-attenuated 
inversion recovery;  ↓= decrease; ↑= increase 
# Progression occurs when any of the criteria with * is present. 
NA**: Increase in corticosteroids alone will not be taken into account in determining progression 
in the absence of persistent clinical deterioration. 
 
 
 


Version 5.0 (30-Aug-2022) 
OU-SCC-PI-4G 
46 
 
Appendix C. Macdonald Criteria for Repsonse Assessment Incorporating MRI and 
Clinical Factors  
 
Current Response Criteria for Malignant Gliomas (Macdonald Criteria)  
 
Response 
Criteria 
Complete response 
Requires all of the following: complete disappearance of all 
enhancing measurable and nonmeasurable disease sustained for 
at least 4 weeks; no new lesions; no corticosteroids; and stable or 
improved clinically 
 
Partial response 
Requires all of the following: ≥50% decrease compared with 
baseline in the sum of products of perpendicular diameters of all 
measurable enhancing lesions sustained for at least 4 weeks; 
no new lesions; stable or reduced corticosteroid dose; and stable 
or improved clinically 
 
Stable disease 
Requires all of the following: does not qualify for complete 
response, partial response, or progression; and stable clinically 
 
Progression 
Defined by any of the following: ≥25% increase in sum of the 
products of perpendicular diameters of enhancing lesions; any 
new lesion; or clinical deterioration 
 
 
Source: Macdonald et al., 1990  
 
 


Version 5.0 (30-Aug-2022) 
OU-SCC-PI-4G 
47 
 
Appendix D. ECOG Performance Status* 
GRADE 
ECOG PERFORMANCE STATUS 
0 
Fully active, able to carry on all pre-disease performance without restriction 
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 
2 
Ambulatory and capable of all selfcare but unable to carry out any work activities; up 
and about more than 50% of waking hours 
3 
Capable of only limited selfcare; confined to bed or chair more than 50% of waking 
hours 
4 
Completely disabled; cannot carry on any selfcare; totally confined to bed or chair 
5 
Dead 
*Oken M, Creech R, Tormey D, et al. Toxicity and response criteria of the Eastern Cooperative 
Oncology Group. Am J Clin Oncol. 1982; 5:649-655. 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


Version 5.0 (30-Aug-2022) 
OU-SCC-PI-4G 
48 
 
Appendix E. GSK Pregnancy Notification Form
 


Version 5.0 (30-Aug-2022) 
OU-SCC-PI-4G 
49 
 
 


Version 5.0 (30-Aug-2022) 
OU-SCC-PI-4G 
50 
 
Appendix F. GSK Pregnancy Follow-up Form 
 


Version 5.0 (30-Aug-2022) 
OU-SCC-PI-4G 
51 
 
 


Version 5.0 (30-Aug-2022) 
OU-SCC-PI-4G 
52 
 
Appendix G. GSK SAE Report Form   
 
 


Version 5.0 (30-Aug-2022) 
OU-SCC-PI-4G 
53 
 
 
 
 
 
 
 
 
 


Version 5.0 (30-Aug-2022) 
OU-SCC-PI-4G 
54 
 
 
 
 
 
 
 
 
 
 
 
 


Version 5.0 (30-Aug-2022) 
OU-SCC-PI-4G 
55 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


Version 5.0 (30-Aug-2022) 
OU-SCC-PI-4G 
56 
 
 
 
 
 
 


Version 5.0 (30-Aug-2022) 
OU-SCC-PI-4G 
57 
 
 

SAP_001.pdf: 
OU-SCC-PI-4G 
STATISTICAL ANALYSIS PLAN 
 
Phase II Trial of Niraparib in Patients with Recurrent Glioma 
Version 2.0 
Version date: January 1 2024 
 
 
Sponsor:  
The University of Oklahoma Health Sciences Center      
Stephenson Cancer Center 
 
800 NE 10th Street 
 
Oklahoma City, OK 73104 
Funding Collaborator: 
GSK Inc.  
Principal Investigator: 
James Battiste, MD, PhD 
 
 
 
 
Neuro-Oncology 
 
 
 
 
Stephenson Cancer Center 
 
 
 
 
800 NE 10th Street, Oklahoma City, OK 73104 
Co-Investigators: 
 
Maya Hrachova, MD 
Neuro-Oncology, Stephenson Cancer Center 
800 NE 10th Street, Oklahoma City, OK 73104 
 
 
 
 
 
Michael Pearlman, MD, PhD 
Blue Sky Neurology 
499 E Hampden Ave Ste 360, Englewood, CO 80113 
Biostatistician  
 
Daniel Zhao, PhD  
SAP Author:  
 
Andrew Cohoon, MPH 
Investigational Product:  
Niraparib  
Protocol Number:  
 
OU-SCC-PI-4G  
NCT Number: 
 
NCT05297864 
 
 


OU-SCC-PI-4G 
Abbreviations 
 
cOR 
 
Clinical response 
CR 
 
Complete response 
DLT 
 
Dose limiting toxicity 
EOS 
 
End of study 
iCRS 
 
Interval cyto-reduction surgery 
MTD 
 
Maximum tolerated dose 
NACT  
Neoadjuvant chemotherapy 
OS 
 
Overall survival 
pCR 
 
Pathological complete response 
PFS 
 
Progression free survival 
PK 
 
Pharmacokinetics 
PR 
 
Partial response 
Q BIW  
Twice a week 
SAP 
 
Statistical analysis plan 
 
 


OU-SCC-PI-4G 
Contents 
 
1. 
Objectives.............................................................................................................................................. 4 
a. 
Primary Objectives ............................................................................................................................ 4 
b. 
Major Secondary Objectives ............................................................................................................. 4 
c. 
Translational Research Objectives ..................................................... Error! Bookmark not defined. 
2. 
Design information ............................................................................................................................... 5 
a. 
General statistical considerations ..................................................................................................... 5 
b. 
Sample Size and Power ..................................................................................................................... 5 
3. 
Study Populations ................................................................................................................................. 5 
a. 
Eligible Patients .................................................................................. Error! Bookmark not defined. 
b. 
Inclusion Criteria ............................................................................................................................... 5 
c. 
Exclusion Criteria ............................................................................................................................... 6 
4. 
Analysis Populations ............................................................................................................................. 7 
5. 
MTD and DLT Analysis (Objective 1.a.i) ................................................. Error! Bookmark not defined. 
a. 
Data needed ....................................................................................... Error! Bookmark not defined. 
b. 
Statistical analysis .............................................................................. Error! Bookmark not defined. 
6. 
Summary of Study Population .............................................................................................................. 8 
a. 
Patient Disposition ............................................................................................................................ 8 
b. 
Demographic and Baseline Characteristics ....................................................................................... 8 
c. 
Medical History and Cancer History.................................................................................................. 8 
d. 
Study Drug Administration and Compliance ..................................................................................... 8 
7. 
Safety Analyses ..................................................................................................................................... 8 
a. 
Adverse Events .................................................................................................................................. 8 
b. 
Laboratory Abnormalities ................................................................................................................. 9 
c. 
Other Safety Assessments ................................................................................................................ 9 
8. 
Pharmacokinetics ................................................................................... Error! Bookmark not defined. 
9. 
Biomarkers ............................................................................................................................................ 9 
10. Antitumor Evaluation ............................................................................................................................ 9 
11. Handling of Missing Data .................................................................................................................... 10 
 
 
 
 


OU-SCC-PI-4G 
 
 
1. Objectives 
a. Primary Objectives  
i. For safety lead-in phase: To evaluate the safety and tolerability of niraparib using 
RADAR-based dosing in patients with recurrent brain tumor.   
ii. For Phase II Dose Expansion Cohorts: To evaluate the efficacy of niraparib in 
patients with recurrent brain tumor using Response Assessment in Neuro-Oncology 
Criteria (RANO); and to evaluate the safety of niraparib in patients with recurrent 
brain tumor at safety lead-in dose.   
 
b. Secondary Objectives  
i. To evaluate Progression free survival (PFS) and overall survival (OS) time for patients 
enrolled in dose expansion cohorts 
ii. To evaluate the duration of disease control (DDC) in patients enrolled on study. 
c. Exploratory Objectives 
i. To identify potential biomarkers associated with tumor response to niraparib based 
on the molecular profile of tumor tissue biomarkers. 
ii. To correlate homologous recombination deficiency (HRD) score obtained via 
myChoice test (Myriad Genetics) with other biomarkers such as IDH1/IDH2 mutation 
and with treatment outcomes. 
 
2. Study Endpoints 
a. Primary End points 
i. For safety lead-in dose and expansion cohorts, monitor safety and tolerability of 
niraparib with individualized starting dose (ISD) in patients with recurrent brain 
tumor. Determination of safety will utilize adverse event occurrence monitoring and 
grade using CTCAE v5.0. 
ii. For Phase II dose expansion cohorts, define the anti-cancer efficacy of niraparib in 
patients with recurrent brain tumor by disease control rate (DCR; complete and 
partial response, and stable disease) as assessed by the RANO. DCR is the 
percentage of patients with a SD or better from start of treatment (cycle 1, day 1) to 
3 months, 6 months, 9 months, and 12 months per RANO. 
 
b. Secondary Endpoints 
i. Anticipate to have prolonged PFS and OS for patients enrolled in dose expansion 
cohorts 
ii. DDC is elapsed time from the first documented CR, PR, pathological CR, or SD until 
first documentation of disease progression or death, whichever comes first. 
 
c. Exploratory Endpoints 
i. Obtain preliminary data about the molecular profile of tumor tissue biomarkers and 
their association with tumor response to niraparib. 
ii. Obtain preliminary data about the association of HRD status with other biomarkers 
and with the anti-cancer effect of niraparib. 


OU-SCC-PI-4G 
3. Design information 
a. General statistical considerations 
 
This is a single arm phase II trial of niraparib in patients with recurrent gliomas. Three to 
six patients will be enrolled in the safety lead-in phase with RADAR dosing. If no SAEs are 
observed in the first 3 patients, then the study will move on to the dose expansion. If 1/3 
patients experience an SAE that is determined to be significant by the PI and medical monitor, 
the same dose will be expanded to 3 more patients. A safety review will be conducted following 
the treatment of the first three or all six patients to determine the niraparib dose for the dose 
expansion phase. Patients enrolled in the safety lead-in phase will be included in the dose-
expansion phase. The starting dose of niraparib for the safety lead-in phase will depend on 
baseline platelet count and weight. 
 
b. Sample Size and Power 
 
This phase II study consists of a safety lead-in and a dose-expansion phase. In the safety 
lead-in phase, three or six patients will be enrolled depending on the safety profile. A total of 45 
evaluable patients (including those from the safety lead-in phase), evenly distributed among 3 
gliomas including GBM, Astrocytoma, and Oligodendroglioma, will be enrolled into dose-
expansion phase. The sample sizes were not computed based on formal statistical power 
calculation. 
 
4. Study Populations 
Inclusion and exclusion criteria are sometimes modified during the duration of the protocol.  Before 
beginning analysis, the statistical team will review the criteria in the SAP to confirm it is up to date 
with the current criteria. 
a. Inclusion Criteria 
i. Patients must be able to understand and willing to sign the informed consent form. 
ii. Patients must be ≥ 18 years of age. 
iii. Patients must have histologically proven high grade gliomas - GBM, Astrocytoma, or 
Oligodendroglioma (glioma WHO Grade III or IV) that is now recurrent by MRI or 
surgical pathology. If there is clinical evidence (such as MRI contrast enhancement) 
that supports a Grade 3 diagnosis of the glioma, the patient will be eligible for the 
study (even if the initial diagnosis was a Grade 2). 
iv. Patients must have measurable or evaluable lesions by RANO. 
v. Eastern Cooperative Oncology Group (ECOG) performance status of 0-2tients must 
be able to understand and willing to sign the informed consent form. 
vi. Patient has archival tumor tissue available; or a fresh biopsy of recurrent or 
persistent tumor must be obtained for molecular assay by myChoice test (Myriad 
Genetics) prior to study treatment initiation. Patient will be requested to share 
reports from any prior genetic testing with the study investigators. 
vii. Participants have systolic BP< 140 mmHg or diastolic BP <90 mmHg that has been 
adequately treated or controlled. 
viii. Have adequate organ function defined by ANC > 1500 cells/mcl, platelets > 
100,000/mcl, Hemoglobin ≥ 9 g/dL, calculated creatinine clearance ≥ 50 mL/min (by 
Cockcroft-Gault formula); total bilirubin < 1.5 times ULN, alanine aminotransferase 
(ALT) and aspartate aminotransferase (AST) levels < 2.5 x ULN. 
ix. Be able to take oral medications 


OU-SCC-PI-4G 
x. Life expectancy ≥ 3 months, allowing adequate follow up of toxicity evaluation and 
antitumor activity; 
xi. Female patient, if of childbearing potential, has a negative serum pregnancy test 
within 72 hours of taking study medication and agrees to abstain from activities that 
could result in pregnancy from enrollment through 180 days after the last dose of 
study treatment or is of nonchildbearing potential. Nonchildbearing potential is 
defined as follows (by other than medical reasons): 
1. ≥45 years of age and has not had menses for >1 year 
2. Patients who have been amenorrhoeic for <2 years without history of a 
hysterectomy and oophorectomy must have a follicle stimulating hormone 
value in the postmenopausal range upon screening evaluation 
3. Post-hysterectomy, post-bilateral oophorectomy, or post-tubal ligation. 
Verbal confirmation of hysterectomy, oophorectomy, or tubal ligation from 
the patient of non-childbearing potential to study staff is sufficient in lieu of 
records from actual procedure and/or confirmation by ultrasound. In this 
case, the patient must be willing to use two adequate barrier methods 
throughout the study, starting with the screening visit through 180 days 
after the last dose of study treatment. This information must be captured 
appropriately within the site’s source documents. Note: Abstinence is 
acceptable if this is the established and preferred contraception for the 
patient. 
xii. Male participant agrees to use an adequate method of contraception starting with 
the first dose of study treatment through 180 days after the last dose of study 
treatment. Note: Abstinence is acceptable if this is the established and preferred 
contraception for the patient. 
1. In addition, men must not donate sperm during niraparib therapy and for 90 
days after receiving the last dose of niraparib. 
xiii. Patient must agree to not breastfeed during the study or for 30 days after the last 
dose of study treatment. 
xiv. Participant must agree to not donate blood during the study or for 90 days after the 
last dose of study treatment. 
xv. Participant receiving systemic corticosteroids may continue as long as their dose is 
stable for at least 4 weeks prior to initiating protocol therapy. Topical and nasal 
steroids are not considered contraindicative and may be used. 
b. Exclusion Criteria 
i. Patient has a known additional malignancy that progressed or required active 
treatment within the last 3 years (exceptions include basal cell carcinoma of the 
skin, squamous cell carcinoma of the skin that has undergone potentially curative 
therapy, or in situ cervical cancer). 
ii. Prior treatment with a known poly(ADP-ribose) polymerase (PARP) inhibitor 
iii. Participants with human immunodeficiency virus (HIV) with detectable viral load. 
Participants with HIV on effective anti-retroviral therapy with documented 
undetectable viral load and CD4 count ≥ 350 within 6 months of the first dose of 
study treatment are eligible for this trial. 
iv. Known active hepatitis B or hepatitis C. 
v. Known history of myelodysplastic syndrome (MDS) or acute myeloid leukemia 
(AML). 


OU-SCC-PI-4G 
vi. Participant is pregnant or expecting to conceive while receiving study treatment 
and/or for up to 180 days after the last dose of study treatment. 
vii. Patient currently participating and receiving study therapy or has participated in a 
study of an investigational agent and received study therapy or used an 
investigational device within 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 dose of 
study drug. 
viii. Received prior anticancer therapy (chemotherapy, targeted therapies, radiotherapy, 
or immunotherapy) within 4 weeks. 
ix. Patients must not have a known hypersensitivity to the components of niraparib or 
the excipients (lactose monohydrate and magnesium stearate). 
x. Patients must not have had major surgery within 4 weeks (including craniotomy) of 
starting the study and patient must have recovered from any effects of any major 
surgery. Stereotactic biopsy by burr hole is considered a minor surgery, and those 
patients undergoing this surgery will be eligible for the study 2 weeks post-
procedure. 
xi. Patients must not have had radiotherapy encompassing > 20% of the bone marrow 
within 2 weeks; or any radiation therapy within 1 week prior to Day 1 of protocol 
therapy. 
xii. Patients must not have received a transfusion (platelets or red blood cells), colony 
stimulating factors (eg, granulocyte colony-stimulating factor, granulocyte 
macrophage colony stimulating factor, or recombinant erythropoietin) ≤ 4 weeks of 
the first dose of study treatment. 
xiii. Patient has had any known Grade 3 or 4 anemia, neutropenia or thrombocytopenia 
due to prior chemotherapy that persisted > 4 weeks and was related to the most 
recent treatment. 
xiv. Participants have any clinically significant gastrointestinal abnormalities that may 
alter absorption such as malabsorption syndrome or major resection of the stomach 
and/or bowels. 
xv. Participants have received live vaccine within 30 days of planned start of study 
randomization. 
xvi. Patients have 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, or any psychiatric disorder that 
prohibits obtaining informed consent 
xvii. Any medical condition not yet specified above that is considered to possibly, 
probably or definitely interfere with study procedures, including adequate follow-up 
and compliance and/or would jeopardize safe treatment. 
5. Analysis Populations 
 
The safety lead-in and dose-expansion phases will be statistically analyzed separately.  The 
safety lead-in phase analysis population will include all patients who have received at least one 
dose of niraparib. 
 
The analysis populations in the dose-expansion phase are defined as below. 


OU-SCC-PI-4G 
• Safety population: All patients who receive at least one dose of niraparib will be included in 
the analyses of compliance and safety.   
• Biomarker population: For biomarker analysis, the biomarker population will comprise all 
patients who have sufficient baseline measurements. 
• Efficacy Evaluable population: For tumor response analysis, the evaluable population will 
comprise all patients who have sufficient baseline and on-study measurements of tumor 
response parameters. 
6. Summary of Study Population 
a. Patient Disposition 
i. Patient disposition will be summarized and include the number dosed, the number 
in each patient population for analysis, the number who withdrew prior to 
completing the study and reason(s) for withdrawal. 
b. Demographic and Baseline Characteristics 
i. Patient demographic and characteristics at study entry will be summarized with 
frequency tables for categorical variables, and with descriptive statistics such as the 
mean, standard deviation, median, and range as appropriate, for quantitative 
variables. 
c. Medical History and Cancer History 
i. Medical history will be coded using the Medical Dictionary for Regulatory Activities 
(MedDRA) version 18 or higher. The count and percentage of subjects under each 
history term, coded by system organ class (SOC) and preferred term (PT), will be 
summarized. 
ii. Cancer history data will also be summarized, including the primary site of cancer, 
the stage and grade of cancer at study entry, time from initial diagnosis of cancer to 
Day 1 of the study in days, duration of metastatic disease in days (first dose date – 
date of diagnosis of metastatic disease + 1), the extent of metastatic disease, and 
the histology. 
d. Study Drug Administration and Compliance 
i. Study drug administration will be summarized in terms of the actual doses 
administered and the proportion of drug actually taken relative to the amount that 
should have been taken; these data will be summarized in frequency distributions 
by cycle and dose level.  The total number of cycles administered; the median 
(range) of cycles administered; dose modifications, dose delays, and dose omissions; 
and reasons for deviations from planned therapy will be summarized by dose level.   
 
7. Safety Analyses 
a. Adverse Events 
i. Adverse events will be tabulated using MedDRA v20.1. The severity of the AE will be 
graded by the Investigator using the NCI CTCAE, version 5.0. The frequency of 
patients experiencing a specific AE will be tabulated by dose level, cycle, system 
organ class, preferred term, seriousness, worst severity, timing of occurrence, 
outcome, and relationship to study drug.  In addition, the number and percentage of 
patients experiencing a specific AE will be tabulated similarly.   


OU-SCC-PI-4G 
b. Laboratory Abnormalities 
i. The severity of laboratory abnormalities will be graded using the NCI CTCAE, version 
5.0, whenever possible.  The frequency of patients experiencing a specific laboratory 
abnormality will be tabulated by dose level, cycle, worst severity, and timing of 
occurrence.  In addition, the number and percentage of patients experiencing a 
specific laboratory abnormality will be summarized similarly. 
c. Other Safety Assessments 
i. The results of vital sign measurements, body weight assessments, ECOG 
performance status determinations and physical examinations will be summarized 
by cycle and dose level, using appropriate descriptive statistics. 
8. Biomarkers 
i. Data of molecular profile from myChoice test will be collected. The tumor 
biomarkers from tumor biopsies, such as HRD, IDH1 /IDH2 mutation and PARP in 
tumor, will be summarized for each patient. 
9. Antitumor Evaluation 
i. The statistical analysis for the dose-expansion phase will be performed by the types 
of gliomas. The objective tumor response (complete and partial response) will be 
summarized as the proportion (and 95% exact Clopper-Pearson CI) of patients with 
a tumor response. The duration of response   by RANO will be summarized 
descriptively using Kaplan-Meier method. Results will be presented in tabular and 
graphic form, as appropriate. The response rate will be compared between 
biomarker status using the chi-squared test or Fisher’s Exact were appropriate.   
ii. Progression-Free Survival (PFS) time is defined as the time from date of study entry 
to the earliest date of progression based on RANO, death (due to tumor 
progression) or date of last contact. Patients who are still alive without progression 
at End of Study (EOS) will be censored on the date of the last evaluable response 
assessment that is not progressive disease (PD). Six-month PFS rate is defined as the 
percentage of patients who are alive and progression-free at 6-month from the start 
of study treatment; with tumor response including CR, PR and SD (estimated by the 
Kaplan-Meier method). PFS will be compared between biomarker status using the 
log-rank test. 
 
Survival curve for PFS will be generated using the Kaplan-Meier method.  Median 
PFS with 95% CI will be computed. 
iii. Overall survival (OS) time is defined as the time from date of study entry to death by 
any cause. Patients who are still alive at EOS are censored on the date they were 
last known to be alive.  Patients who are still alive at EOS or whose vital status is 
unknown, will be censored at the last date of contact.  An exploratory analysis to 
determine 6 months or 9 months OS rate will be estimated by the Kaplan-Meier 
method. OS will be compared between biomarker status using the log-rank test. 
 
Survival curve for OS will be generated using the Kaplan-Meier method.  Median OS 
with 95% CI will be computed. 


OU-SCC-PI-4G 
10. Handling of Missing Data 
Every effort will be made to collect information at all defined visits including at early withdrawal or 
dropout. Reasons for missing data will be summarized. However, there will be no imputation of 
missing data.