A Study of Niraparib in Patients With Ovarian Cancer Who Have Received Three or Four Previous Chemotherapy Regimens

A Phase 2, Open-Label, Single-Arm Study to Evaluate the Safety and Efficacy of Niraparib in Patients With Advanced, Relapsed, High-Grade Serous Epithelial Ovarian, Fallopian Tube, or Primary Peritoneal Cancer Who Have Received Three or Four Previous Chemotherapy Regimens

Status

Completed

Phases

Phase 2

Study type

Interventional

Source

ClinicalTrials.gov

Registry ID

NCT02354586

Acronym

QUADRA

Enrollment

463

Registered

2015-02-03

Start date

2015-03-23

Completion date

2021-08-23

Last updated

2022-09-15

For informational purposes only — not medical advice. Sourced from public registries and may not reflect the latest updates. Terms

Conditions

Ovarian Cancer, Ovarian Neoplasms

Keywords

gBRCAmut, BRCA, PARP inhibitor, HRD, Ovarian cancer, Serous Epithelial, Fallopian Tube, Primary Peritoneal

Brief summary

This is a Phase 2, open-label, single arm study to evaluate the safety and efficacy of niraparib in ovarian cancer patients who have received three or four previous chemotherapy regimens. Niraparib is an orally active PARP inhibitor. Niraparib will be administered once daily continuously during a 28-day cycle. Health-related quality of life will be measured by Eastern Cooperative Oncology Group performance status (ECOG). Safety and tolerability will be assessed by clinical review of adverse events (AEs), physical examinations, electrocardiograms (ECGs), RECIST tumor assessments and safety laboratory values.

Interventions

DRUGNiraparib

Study design

Allocation

Intervention model

SINGLE_GROUP

Primary purpose

TREATMENT

Masking

NONE

Eligibility

Sex/Gender

FEMALE

Age

18 Years to No maximum

Healthy volunteers

Inclusion criteria

* Patients must agree to undergo tumor HRD testing and blood gBRCAmut status testing. * Patients of childbearing potential must have negative pregnancy serum test within 72 hours of being dosed * Patients must have histologically diagnosed high-grade (Grade 2 or 3) serous epithelial ovarian, fallopian tube, or primary peritoneal cancer with recurrent disease and must have been previously treated with chemotherapy and experienced a response lasting at least 6 months to first-line platinum based therapy. * Patients Must have completed 3 or 4 previous chemotherapy regimens. * Patients must have completed their last chemotherapy regimen \> 4 weeks prior to treatment initiation. * Patients must have measurable disease according to RECIST (v.1.1). * Patients must have formalin-fixed, paraffin-embedded tumor samples available from the primary or recurrent cancer or agree to undergo fresh biopsy prior to study treatment initiation. * Patients must agree to blood samples during screening and at the end of treatment for cytogenetic analysis.

Exclusion criteria

* Patients must not have any known, persistent (\> 4 weeks), ≥Grade 3 hematologic toxicity during the last cancer therapy. Patients must not have any known, persistent (\>4 weeks), ≥ Grade 3 fatigue during the last cancer therapy. * Patients must not have received pelvic radiotherapy as treatment for primary or recurrent disease within 1 year of the first dose of study treatment. * Patients must not have symptomatic uncontrolled brain or leptomeningeal metastases. * Patients must not be considered a poor medical risk due to a serious, uncontrolled medical disorder, nonmalignant systemic disease or active, uncontrolled infection. * Patients must not have received a transfusion (platelets or red blood cells) within 4 weeks of the first dose of study treatment. * Patients must not have known history or current diagnosis of myelodysplastic syndrome (MDS) or acute myeloid leukemia (AML).

Design outcomes

Primary

Measure	Time frame	Description
Objective Response Rate (ORR)	Up to 3 years	The ORR was defined as the percentage of participants achieving complete response (CR) or partial response (PR) as assessed by the Investigator per Response Evaluation Criteria in Solid Tumors (RECIST) (version1.1), where CR=Disappearance of all target lesions. Any pathological lymph nodes must be \<10 millimeters (mm) in the short axis, PR=At least a 30 percent (%) decrease in the sum of the diameters of target lesions, taking as a reference, the Baseline sum of the diameters. Primary Analysis Population comprised of participants who received 3 or 4 prior lines of therapy (LOT), had homologous recombination deficiency positive (HRDpos) tumors, had platinum-sensitive disease, and were poly(adenosine 5'-diphosphate \[ADP\]-ribose) polymerase inhibitors (PARPi) naïve.

Secondary

Measure	Time frame	Description
Duration of Response (DoR)	Up to 3 years	DoR was defined as the time from first documentation of CR or PR until the time of first documentation of disease progression (PD) as assessed by the Investigator per RECIST (version1.1). DoR was analyzed using Kaplan-Meier (KM) method.
ORR by HRD Status and Breast Cancer Gene (BRCA) Status	Up to 3 years	The ORR was defined as the percentage of participants achieving CR or PR as assessed by the Investigator per RECIST (version1.1), where CR=Disappearance of all target lesions. Any pathological lymph nodes must be \<10 mm in the short axis. PR=At least a 30% decrease in the sum of the diameters of target lesions, taking as a reference, the Baseline sum of the diameters. ORR was evaluated for participants with following characteristics: HRD status (positive, negative and unknown) and BRCA status (mutation positive, wild-type and unknown).
Disease Control Rate (DCR)	Up to 3 years	Disease control rate was defined as the percentage of participants achieving CR, PR, or stable disease (SD) as assessed by the Investigator per RECIST (version1.1). The exact (Clopper-Pearson) method was used to calculate 95% confidence interval.
Progression Free Survival	Up to 3 years	Progression-free survival was defined as the time from the date of first dose to the earlier date of assessment of progression or death by any cause in the absence of progression as assessed by the Investigator per RECIST (version 1.1) or clinical criteria. Progression is defined using RECIST version1.1 as at least a 20% increase in the sum of the diameter of target lesions or unequivocal progression of existing non-target lesions or the appearance of one or more new lesions.
Overall Survival	Up to 3 years	Overall Survival was defined as the time from the date of the first dose to the date of death by any cause. It was calculated as (Date of Death minus First dose date plus 1) divided by 30.4375.
Time to First Subsequent Therapy (TFST)	Up to 3 years	Time to first subsequent therapy (TFST) was defined as the time from the date of first dose to the date of first subsequent therapy or death, whichever occurs first. It was calculated as (Earlier of \[First dose of first subsequent therapy or death\] minus First dose date plus 1) divided by 30.4375.

Other

Measure	Time frame	Description
Number of Participants With Abnormality in Hematology Parameters	Up to 3 years	Number of participants with abnormality in hematology parameters were planned to be analyzed.
Number of Participants With Abnormality in Clinical Chemistry Parameters	Up to 3 years	Number of participants with abnormality in clinical chemistry parameters were planned to be analyzed.
Number of Participants With Abnormality in Vital Signs	Up to 3 years	Number of participants with abnormality in vital signs were planned to be analyzed.
Number of Participants With Abnormality in Physical Examination	Up to 3 years	Number of participants with abnormality in physical examination were planned to be analyzed.
Number of Participants Who Were Administered Concomitant Medications	Up to 3 years	Number of participants who were administered concomitant medications were planned to be analyzed.
Number of Participants With Any Non-serious Adverse Event (Non-SAE) and Any Serious Adverse Event (SAE)	Up to a maximum of 71.56 months	An adverse event is any untoward medical occurrence that occurs in a participant or clinical investigation participant administered a pharmaceutical product, and which does not necessarily have to have a causal relationship with study treatment. Any untoward event resulting in death, life threatening, requires hospitalization or prolongation of existing hospitalization, results in disability/incapacity, congenital anomaly or birth defect or any other situation according to medical or scientific judgment was categorized as SAE. Adverse events which were not serious were considered as Non-serious adverse events.

Countries

Canada, United States

Participant flow

Recruitment details

This was an open-label, single arm study to evaluate the safety and efficacy of niraparib in ovarian cancer participants who have received previous chemotherapy regimens.

Pre-assignment details

A total of 463 participants were enrolled in the study (Safety Population was comprised of all participants who received at least 1 dose of study drug).

Participants by arm

Arm	Count
Niraparib 300 mg Participants received Niraparib (300 milligram \[mg\], taken as 3 capsules of 100 mg once daily \[QD\]) orally beginning on Day 1 of every cycle (28 days) until treatment discontinuation.	463
Total	463

Withdrawals & dropouts

Period	Reason	FG000
Overall Study	Adverse Event	7
Overall Study	Death	230
Overall Study	Intercurrent illness	1
Overall Study	Lack of Efficacy	86
Overall Study	Lost to Follow-up	11
Overall Study	Physician Decision	13
Overall Study	Protocol Violation	3
Overall Study	Site closure	2
Overall Study	Sponsor decision	51
Overall Study	Withdrawal by Subject	59

Baseline characteristics

Characteristic	Niraparib 300 mg
Age, Continuous	64.3 Years STANDARD_DEVIATION 9.28
Race/Ethnicity, Customized American Indian or Alaska Native	1 Participants
Race/Ethnicity, Customized Asian	16 Participants
Race/Ethnicity, Customized Black	20 Participants
Race/Ethnicity, Customized Unknown	32 Participants
Race/Ethnicity, Customized White	394 Participants
Sex: Female, Male Female	463 Participants
Sex: Female, Male Male	0 Participants

Adverse events

Event type	EG000 affected / at risk
deaths Total, all-cause mortality	232 / 463
other Total, other adverse events	461 / 463
serious Total, serious adverse events	200 / 463

Outcome results

Primary

Objective Response Rate (ORR)

The ORR was defined as the percentage of participants achieving complete response (CR) or partial response (PR) as assessed by the Investigator per Response Evaluation Criteria in Solid Tumors (RECIST) (version1.1), where CR=Disappearance of all target lesions. Any pathological lymph nodes must be \<10 millimeters (mm) in the short axis, PR=At least a 30 percent (%) decrease in the sum of the diameters of target lesions, taking as a reference, the Baseline sum of the diameters. Primary Analysis Population comprised of participants who received 3 or 4 prior lines of therapy (LOT), had homologous recombination deficiency positive (HRDpos) tumors, had platinum-sensitive disease, and were poly(adenosine 5'-diphosphate \[ADP\]-ribose) polymerase inhibitors (PARPi) naïve.

Time frame: Up to 3 years

Population: Primary Analysis Population. Only those participants with data available at the specified time points were analyzed.

Arm	Measure	Value (NUMBER)
Niraparib 300 mg	Objective Response Rate (ORR)	27.66 Percentage of participants

Secondary

Disease Control Rate (DCR)

Disease control rate was defined as the percentage of participants achieving CR, PR, or stable disease (SD) as assessed by the Investigator per RECIST (version1.1). The exact (Clopper-Pearson) method was used to calculate 95% confidence interval.

Time frame: Up to 3 years

Population: ITT Population. Only those participants with data available at the specified time points were analyzed.

Arm	Measure	Value (NUMBER)
Niraparib 300 mg	Disease Control Rate (DCR)	49.02 Percentage of participants

Secondary

Duration of Response (DoR)

DoR was defined as the time from first documentation of CR or PR until the time of first documentation of disease progression (PD) as assessed by the Investigator per RECIST (version1.1). DoR was analyzed using Kaplan-Meier (KM) method.

Time frame: Up to 3 years

Population: Intent-to-Treat (ITT) Population was comprised of all dosed participants with measurable disease at Baseline. Measurable disease at Baseline was determined by the existence of at least 1 target lesion at Baseline tumor scan based on investigator's assessment. Only those participants with data available at the specified time points were analyzed.

Arm	Measure	Value (MEDIAN)
Niraparib 300 mg	Duration of Response (DoR)	9.4 Months

Secondary

ORR by HRD Status and Breast Cancer Gene (BRCA) Status

The ORR was defined as the percentage of participants achieving CR or PR as assessed by the Investigator per RECIST (version1.1), where CR=Disappearance of all target lesions. Any pathological lymph nodes must be \<10 mm in the short axis. PR=At least a 30% decrease in the sum of the diameters of target lesions, taking as a reference, the Baseline sum of the diameters. ORR was evaluated for participants with following characteristics: HRD status (positive, negative and unknown) and BRCA status (mutation positive, wild-type and unknown).

Time frame: Up to 3 years

Population: ITT Population. All the participants from the ITT Population were analyzed (461 participants), but only those participants with data available at the specified data points were analyzed (represented by n=X in the category titles).

Arm	Measure	Group	Value (NUMBER)
Niraparib 300 mg	ORR by HRD Status and Breast Cancer Gene (BRCA) Status	HRD positive, n=221	14.0 Percentage of participants
Niraparib 300 mg	ORR by HRD Status and Breast Cancer Gene (BRCA) Status	HRD negative, n=195	2.6 Percentage of participants
Niraparib 300 mg	ORR by HRD Status and Breast Cancer Gene (BRCA) Status	HRD unknown, n=45	6.7 Percentage of participants
Niraparib 300 mg	ORR by HRD Status and Breast Cancer Gene (BRCA) Status	BRCA mutation positive, n=87	23.0 Percentage of participants
Niraparib 300 mg	ORR by HRD Status and Breast Cancer Gene (BRCA) Status	BRCA wild-type, n=317	5.0 Percentage of participants
Niraparib 300 mg	ORR by HRD Status and Breast Cancer Gene (BRCA) Status	BRCA unknown, n=57	5.3 Percentage of participants

Secondary

Overall Survival

Overall Survival was defined as the time from the date of the first dose to the date of death by any cause. It was calculated as (Date of Death minus First dose date plus 1) divided by 30.4375.

Time frame: Up to 3 years

Population: ITT Population. Only those participants with data available at the specified time points were analyzed.

Arm	Measure	Value (MEDIAN)
Niraparib 300 mg	Overall Survival	17.2 Months

Secondary

Progression Free Survival

Progression-free survival was defined as the time from the date of first dose to the earlier date of assessment of progression or death by any cause in the absence of progression as assessed by the Investigator per RECIST (version 1.1) or clinical criteria. Progression is defined using RECIST version1.1 as at least a 20% increase in the sum of the diameter of target lesions or unequivocal progression of existing non-target lesions or the appearance of one or more new lesions.

Time frame: Up to 3 years

Population: ITT Population. Only those participants with data available at the specified time points were analyzed.

Arm	Measure	Value (MEDIAN)
Niraparib 300 mg	Progression Free Survival	3.5 Months

Secondary

Time to First Subsequent Therapy (TFST)

Time to first subsequent therapy (TFST) was defined as the time from the date of first dose to the date of first subsequent therapy or death, whichever occurs first. It was calculated as (Earlier of \[First dose of first subsequent therapy or death\] minus First dose date plus 1) divided by 30.4375.

Time frame: Up to 3 years

Population: ITT Population. Only those participants with data available at the specified time points were analyzed.

Arm	Measure	Value (MEDIAN)
Niraparib 300 mg	Time to First Subsequent Therapy (TFST)	6.8 Months

Other Pre-specified