Neoplasms
Conditions
Keywords
PARP inhibitor, niraparib, Solid Tumor, Zejula
Brief summary
This is a three stage, open label, randomized-sequence, single-crossover Phase 1 study to evaluate the relative bioavailability (BA) and Bioequivalence (BE) of niraparib administered as a tablet formulation compared to the reference capsule formulation currently marketed in the United States. Stage 3 evaluates the effect of a high-fat meal on niraparib pharmacokinetics (PK) following a single dose of the tablet. The Extension Phase of this study is to enable participants enrolled in the study to continue to receive treatment with niraparib tablets if they are tolerating it and, in the Investigator's opinion, may receive benefit.
Interventions
DRUGNiraparib Tablet
Niraparib tablet formulation
DRUGNiraparib Capsule
Niraparib capsule formulation
Sponsors
Tesaro, Inc.
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
Key inclusion criteria: PK Phase: To be considered eligible to participate in this study, all of the following requirements must be met: * Participants with histologically or cytologically confirmed diagnosis of metastatic or locally advanced solid tumors that have failed to respond to standard therapy, has progressed despite standard therapy, or for which no standard therapy exists, and who may benefit from treatment with a poly (adenosine diphosphate-ribose) polymerase (PARP) inhibitor as assessed by the Investigator. * Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 2. * Adequate organ function as defined: Absolute neutrophil count ≥ 1,500 per microliter (/μL) (For Stage 3: \>=1000/μL); Platelets ≥ 100,000/μL; Hemoglobin ≥ 9 grams per deciliter (g/dL) (5.6 millimolar \[mM\]); Serum creatinine ≤ 1.5 × the upper limit of normal (ULN) or a calculated creatinine clearance ≥ 60 milliliters per minute (mL/min) using the Cockcroft-Gault equation or 24-hour urine creatinine clearance.; Total bilirubin ≤ 1.5 × ULN except in participants with Gilbert's syndrome. Participants with Gilbert's syndrome may enroll if direct bilirubin ≤ 1.5 × ULN of the direct bilirubin; Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤ 2.5 × ULN unless liver metastases are present, in which case, they must be ≤ 5 × ULN. * Participant has recovered to Grade 1 toxicity from prior cancer therapy (a participant with Grade 2 neuropathy or Grade 2 alopecia is an exception to this criterion and may qualify for this study). * Female participant of childbearing potential is not breastfeeding, has a negative serum pregnancy test within 72 hours prior to taking study drug and agrees to abstain from activities that could result in pregnancy from Screening through 180 days after the last dose of study drug. * Male participant agrees to use an adequate method of contraception and not donate sperm starting with the first dose of study drug through 90 days after the last dose of study drug. * (For Stage 3): CNS inclusion - Based on screening brain magnetic resonance imaging indicating no evidence of brain metastasis or needing immediate local therapy. * Participant is able to eat a high fat meal. * Participant is able to fast for a minimum of 10 hours before start of visit and for an additional 4 hours after study visit. Extension Phase: * ECOG performance status of 0 to 2. * Adequate organ function as defined: Absolute neutrophil count ≥ 1,500/μL (For Stage 3: \>=1000/μL); Platelets ≥ 100,000/μL; Hemoglobin ≥ 9 g/dL (5.6 mM); serum creatinine ≤ 1.5 × the ULN or a calculated creatinine clearance ≥ 60 mL/min (For Stage 3: ≥ 30 mL/min) using the Cockcroft-Gault equation or 24-hour urine creatinine clearance; Total bilirubin ≤ 1.5 × ULN except in participant with Gilbert's syndrome. Participants with Gilbert's syndrome may enroll if direct bilirubin ≤ 1.5 × ULN of the direct bilirubin; AST and ALT ≤ 2.5 × ULN unless liver metastases are present, in which case, they must be ≤5 × ULN * Female participant of childbearing potential is not breastfeeding, has a negative serum pregnancy test within 72 hours prior to taking study drug and agrees to abstain from activities that could result in pregnancy from Screening through 180 days after the last dose of study drug. * Male participant agrees to use an adequate method of contraception and not donate sperm starting with the first dose of study drug through 90 days after the last dose of study drug. Key
Exclusion criteria
PK Phase: * Known diagnosis of immunodeficiency * Symptomatic uncontrolled brain or leptomeningeal metastases. * Major surgery within 3 weeks of starting the study or participant has not recovered from any effects of any major surgery. * Participant is considered a poor medical risk due to a serious, uncontrolled medical disorder; nonmalignant systemic disease; or active, uncontrolled infection. * Known history of myelodysplastic syndrome or acute myeloid leukemia. * Participant is currently taking any of the following P-glycoprotein (P-gp) inhibitors: amiodarone, azithromycin, captopril, carvedilol, clarithromycin, conivaptan, cyclosporine, diltiazem, dronedarone, erythromycin, felodipine, itraconazole, ketoconazole, lopinavir and ritonavir, quercetin, quinidine, ranolazine, ticagrelor, and verapamil (Does not apply for Extension Phase). * Participant taking proton pump inhibitors, antacids, or histamine 2 blockers within 48 hours prior to study drug administration (Does not apply for Extension Phase). * Participant has gastric, gastro-esophageal or esophageal cancer; participant is unable to swallow orally administered medication; or participant has gastrointestinal disorders or significant gastrointestinal resection likely to interfere with the absorption of niraparib. * Participant has known active hepatic disease * Participant has a past or current history of chronic alcohol use. * Participant has significant pleural effusion or ascites that is expected to require drainage during the PK Phase (Does not apply for Extension Phase). * For Stage 3 only: Participant is currently taking a lipase inhibitor or cholesterol absorption inhibitor, such as orlistat or ezetimibe, respectively. (Does not apply for participation in Extension Phase of this study).
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Time From Administration of the Dose to the First Quantifiable Concentration (Tlag) for Niraparib-Stage 3 PK Phase | Pre-dose, 1, 1.5, 2, 3, 4, 5, 6, 7, 8, 12, 24, 48, 72, 96, 120 and 168 hours post-dose in each treatment period | Blood samples were collected at indicated time points for pharmacokinetic assessment of tlag. Pharmacokinetic parameters were calculated using standard non-compartmental analysis. |
| Vz/F for Niraparib-Stage 2 PK Phase | Pre-dose, 1, 1.5, 2, 3, 4, 5, 6, 7, 8, 12, 24, 48, 72, 96, 120 and 168 hours post-dose in each treatment period | Blood samples were collected at indicated time points for pharmacokinetic assessment of Vz/F. Pharmacokinetic parameters were calculated using standard non-compartmental analysis. |
| AUC(0-t) for Niraparib-Stage 3 PK Phase | Pre-dose, 1, 1.5, 2, 3, 4, 5, 6, 7, 8, 12, 24, 48, 72, 96, 120 and 168 hours post-dose in each treatment period | Blood samples were collected at indicated time points for pharmacokinetic assessment of AUC(0-t). Pharmacokinetic parameters were calculated using standard non-compartmental analysis. |
| AUC(0 to Inf) for Niraparib-Stage 3 PK Phase | Pre-dose, 1, 1.5, 2, 3, 4, 5, 6, 7, 8, 12, 24, 48, 72, 96, 120 and 168 hours post-dose in each treatment period | Blood samples were collected at indicated time points for pharmacokinetic assessment of AUC(0 to inf). Pharmacokinetic parameters were calculated using standard non-compartmental analysis. |
| Cmax for Niraparib-Stage 3 PK Phase | Pre-dose, 1, 1.5, 2, 3, 4, 5, 6, 7, 8, 12, 24, 48, 72, 96, 120 and 168 hours post-dose in each treatment period | Blood samples were collected at indicated time points for pharmacokinetic assessment of Cmax. Pharmacokinetic parameters were calculated using standard non-compartmental analysis. |
| Tmax for Niraparib-Stage 3 PK Phase | Pre-dose, 1, 1.5, 2, 3, 4, 5, 6, 7, 8, 12, 24, 48, 72, 96, 120 and 168 hours post-dose in each treatment period | Blood samples were collected at indicated time points for pharmacokinetic assessment of Tmax. Pharmacokinetic parameters were calculated using standard non-compartmental analysis. |
| T1/2 for Niraparib-Stage 3 PK Phase | Pre-dose, 1, 1.5, 2, 3, 4, 5, 6, 7, 8, 12, 24, 48, 72, 96, 120 and 168 hours post-dose in each treatment period | Blood samples were collected at indicated time points for pharmacokinetic assessment of T1/2. Pharmacokinetic parameters were calculated using standard non-compartmental analysis. |
| CL/F for Niraparib-Stage 3 PK Phase | Pre-dose, 1, 1.5, 2, 3, 4, 5, 6, 7, 8, 12, 24, 48, 72, 96, 120 and 168 hours post-dose in each treatment period | Blood samples were collected at indicated time points for pharmacokinetic assessment of CL/F. Pharmacokinetic parameters were calculated using standard non-compartmental analysis. |
| Vz/F for Niraparib-Stage 3 PK Phase | Pre-dose, 1, 1.5, 2, 3, 4, 5, 6, 7, 8, 12, 24, 48, 72, 96, 120 and 168 hours post-dose in each treatment period | Blood samples were collected at indicated time points for pharmacokinetic assessment of Vz/F. Pharmacokinetic parameters were calculated using standard non-compartmental analysis. |
| Area Under the Concentration-time Curve From Time 0 to the Time of the Last Quantifiable Concentration (AUC[0-t]) for Niraparib-Stage 1 PK Phase | Pre-dose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24, 48, 72, 96, 120 and 168 hours post-dose in each treatment period | Blood samples were collected at indicated time points for pharmacokinetic assessment of AUC(0-t). Pharmacokinetic parameters were calculated using standard non-compartmental analysis. |
| Area Under the Concentration-time Curve From Time 0 Extrapolated to Infinity (AUC[0 to Inf]) for Niraparib-Stage 1 PK Phase | Pre-dose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24, 48, 72, 96, 120 and 168 hours post-dose in each treatment period | Blood samples were collected at indicated time points for pharmacokinetic assessment of AUC(0 to inf). Pharmacokinetic parameters were calculated using standard non-compartmental analysis. |
| Maximum Observed Plasma Concentration (Cmax) for Niraparib-Stage 1 PK Phase | Pre-dose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24, 48, 72, 96, 120 and 168 hours post-dose in each treatment period | Blood samples were collected at indicated time points for pharmacokinetic assessment of Cmax. Pharmacokinetic parameters were calculated using standard non-compartmental analysis. |
| Time to Reach Maximum Observed Plasma Concentration (Tmax) for Niraparib-Stage 1 PK Phase | Pre-dose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24, 48, 72, 96, 120 and 168 hours post-dose in each treatment period | Blood samples were collected at indicated time points for pharmacokinetic assessment of Tmax. Pharmacokinetic parameters were calculated using standard non-compartmental analysis. |
| Terminal Half-life (T1/2) for Niraparib-Stage 1 PK Phase | Pre-dose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24, 48, 72, 96, 120 and 168 hours post-dose in each treatment period | Blood samples were collected at indicated time points for pharmacokinetic assessment of T1/2. Pharmacokinetic parameters were calculated using standard non-compartmental analysis. |
| Apparent Total Body Clearance (CL/F) for Niraparib-Stage 1 PK Phase | Pre-dose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24, 48, 72, 96, 120 and 168 hours post-dose in each treatment period | Blood samples were collected at indicated time points for pharmacokinetic assessment of CL/F. Pharmacokinetic parameters were calculated using standard non-compartmental analysis. |
| Apparent Terminal Volume of Distribution (Vz/F) for Niraparib-Stage 1 PK Phase | Pre-dose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24, 48, 72, 96, 120 and 168 hours post-dose in each treatment period | Blood samples were collected at indicated time points for pharmacokinetic assessment of Vz/F. Pharmacokinetic parameters were calculated using standard non-compartmental analysis. |
| AUC(0-t) for Niraparib-Stage 2 PK Phase | Pre-dose, 1, 1.5, 2, 3, 4, 5, 6, 7, 8, 12, 24, 48, 72, 96, 120 and 168 hours post-dose in each treatment period | Blood samples were collected at indicated time points for pharmacokinetic assessment of AUC(0-t). Pharmacokinetic parameters were calculated using standard non-compartmental analysis. |
| AUC(0 to Inf) for Niraparib-Stage 2 PK Phase | Pre-dose, 1, 1.5, 2, 3, 4, 5, 6, 7, 8, 12, 24, 48, 72, 96, 120 and 168 hours post-dose in each treatment period | Blood samples were collected at indicated time points for pharmacokinetic assessment of AUC(0 to inf). Pharmacokinetic parameters were calculated using standard non-compartmental analysis. |
| Cmax for Niraparib-Stage 2 PK Phase | Pre-dose, 1, 1.5, 2, 3, 4, 5, 6, 7, 8, 12, 24, 48, 72, 96, 120 and 168 hours post-dose in each treatment period | Blood samples were collected at indicated time points for pharmacokinetic assessment of Cmax. Pharmacokinetic parameters were calculated using standard non-compartmental analysis. |
| Tmax for Niraparib-Stage 2 PK Phase | Pre-dose, 1, 1.5, 2, 3, 4, 5, 6, 7, 8, 12, 24, 48, 72, 96, 120 and 168 hours post-dose in each treatment period | Blood samples were collected at indicated time points for pharmacokinetic assessment of Tmax. Pharmacokinetic parameters were calculated using standard non-compartmental analysis. |
| T1/2 for Niraparib-Stage 2 PK Phase | Pre-dose, 1, 1.5, 2, 3, 4, 5, 6, 7, 8, 12, 24, 48, 72, 96, 120 and 168 hours post-dose in each treatment period | Blood samples were collected at indicated time points for pharmacokinetic assessment of T1/2. Pharmacokinetic parameters were calculated using standard non-compartmental analysis. |
| CL/F for Niraparib-Stage 2 PK Phase | Pre-dose, 1, 1.5, 2, 3, 4, 5, 6, 7, 8, 12, 24, 48, 72, 96, 120 and 168 hours post-dose in each treatment period | Blood samples were collected at indicated time points for pharmacokinetic assessment of CL/F. Pharmacokinetic parameters were calculated using standard non-compartmental analysis. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With TEAEs Leading to Discontinuation -Stage 1 PK Phase (Periods 1 and 2 Only) | Up to 16 days | An adverse event is any untoward medical occurrence in a clinical investigation participant administered a medicinal product and which does not necessarily have a causal relationship with this treatment. TEAE is any event that was not present prior to the initiation of study treatment or any event already present that worsens in either intensity or frequency following exposure to study treatment. Number of participants with TEAEs leading to discontinuation is reported. TEAEs reported under Niraparib tablet and Niraparib capsule arms include TEAEs with onset date during the corresponding period (Period 1 or Period 2) in which the participant received niraparib tablet and capsule, respectively. |
| Number of Participants With TEAEs and Serious TEAEs-Stage 2 PK Phase (Periods 1 and 2 Only) | Up to 24 days | An adverse event is any untoward medical occurrence in a clinical investigation participant administered a medicinal product and which does not necessarily have a causal relationship with this treatment. An SAE is any untoward medical occurrence that, at any dose; results in death; is life threatening; requires inpatient hospitalization or prolongation of existing hospitalization; results in persistent or significant disability/incapacity; is a congenital anomaly/birth defect; or is an important medical event. TEAE is any event that was not present prior to the initiation of study treatment or any event already present that worsens in either intensity or frequency following exposure to study treatment. TEAEs reported under Niraparib tablet and Niraparib capsule arms include TEAEs with onset date during the corresponding period (Period 1 or Period 2) in which the participant received niraparib tablet and capsule, respectively. |
| Number of Participants With TEAEs-leading to Discontinuation Stage 2 PK Phase (Periods 1 and 2 Only) | Up to 24 days | An adverse event is any untoward medical occurrence in a clinical investigation participant administered a medicinal product and which does not necessarily have a causal relationship with this treatment. Number of participants with TEAEs leading to discontinuation is reported. TEAEs reported under Niraparib tablet and Niraparib capsule arms include TEAEs with onset date during the corresponding period (Period 1 or Period 2) in which the participant received niraparib tablet and capsule, respectively. |
| Number of Participants With TEAEs and Serious TEAEs-Stage 3 PK Phase (Periods 1 and 2 Only) | Up to 45 days | An adverse event is any untoward medical occurrence in a clinical investigation participant administered a medicinal product and which does not necessarily have a causal relationship with this treatment. An SAE is any untoward medical occurrence that, at any dose; results in death; is life threatening; requires inpatient hospitalization or prolongation of existing hospitalization; results in persistent or significant disability/incapacity; is a congenital anomaly/birth defect; or is an important medical event. TEAE is any event that was not present prior to the initiation of study treatment or any event already present that worsens in either intensity or frequency following exposure to study treatment. TEAEs reported under Niraparib tablets under fasted and fed arms include TEAEs with onset date during the corresponding period (Period 1 or Period 2) in which the participant received niraparib tablet fasted and fed, respectively. |
| Number of Participants With TEAEs-leading to Discontinuation Stage 3 PK Phase (Periods 1 and 2 Only) | Up to 45 days | An adverse event is any untoward medical occurrence in a clinical investigation participant administered a medicinal product and which does not necessarily have a causal relationship with this treatment. Number of participants with TEAEs leading to discontinuation is reported. TEAEs reported under Niraparib tablets under fasted and fed arms include TEAEs with onset date during the corresponding period (Period 1 or Period 2) in which the participant received niraparib tablet fasted and fed, respectively. |
| Number of Participants With TEAEs and Serious TEAEs - Extension Phase | Up to approximately 5 years 5 months | An adverse event is any untoward medical occurrence in a clinical investigation participant administered a medicinal product and which does not necessarily have a causal relationship with this treatment. An SAE is any untoward medical occurrence that, at any dose; results in death; is life threatening; requires inpatient hospitalization or prolongation of existing hospitalization; results in persistent or significant disability/incapacity; is a congenital anomaly/birth defect; or is an important medical event. TEAE is any event that was not present prior to the initiation of study treatment or any event already present that worsens in either intensity or frequency following exposure to study treatment. A summary of number of participants with any TEAEs and serious TEAEs is presented. Serious TEAEs are subset of TEAEs. TEAEs were coded using the Medical Dictionary for Regulatory Affairs (MedDRA dictionary). |
| Number of Participants With TEAEs-leading to Discontinuation - Extension Phase | Up to approximately 5 years 5 months | An adverse event is any untoward medical occurrence in a clinical investigation participant administered a medicinal product and which does not necessarily have a causal relationship with this treatment. TEAE is any event that was not present prior to the initiation of study treatment or any event already present that worsens in either intensity or frequency following exposure to study treatment. A summary of number of participants who discontinued due to any TEAEs is presented. TEAEs were coded using the Medical Dictionary for Regulatory Affairs (MedDRA dictionary). |
| Number of Participants With Treatment Emergent Adverse Events (TEAEs) and Serious TEAEs-Stage 1 PK Phase (Periods 1 and 2 Only) | Up to 16 days | An adverse event is any untoward medical occurrence in a clinical investigation participant administered a medicinal product and which does not necessarily have a causal relationship with this treatment. A serious adverse event (SAE) is any untoward medical occurrence that, at any dose; results in death; is life threatening; requires inpatient hospitalization or prolongation of existing hospitalization; results in persistent or significant disability/incapacity; is a congenital anomaly/birth defect; or is an important medical event. TEAE is any event that was not present prior to the initiation of study treatment or any event already present that worsens in either intensity or frequency following exposure to study treatment. TEAEs reported under Niraparib tablet and Niraparib capsule arms include TEAEs with onset date during the corresponding period (Period 1 or Period 2) in which the participant received niraparib tablet and capsule, respectively. |
Countries
United States
Participant flow
Recruitment details
This was a 3-stage, single cross-over study. The study had a pharmacokinetic (PK) phase consisting of stages 1, 2, and 3 and an Extension Phase. The Extension Phase based on Investigator and Sponsor's decision provided qualifying participants continued access to niraparib therapy.
Pre-assignment details
A total of 236 participants were enrolled. The Safety Population comprised all participants who received any amount of niraparib during the PK Phase and Extension Phase of the study.
Participants by arm
| Arm | Count |
|---|---|
| Stage 1: Niraparib Tablet/Capsule Participants received a single oral dose of 300 milligrams (mg) niraparib tablet in a fasted state in Period 1, followed by a wash-out period of 7 days. In Period 2, participants received a single oral dose of 3 capsules of 100 mg niraparib in a fasted state followed by a 7-day wash-out period. After the last dose of niraparib, participants who did not enter the Extension Phase were followed for up to 30 days (safety follow-up \[f/u\]) while participants eligible for Extension Phase proceeded for Extension Phase screening. Eligible participants then entered the Extension Phase, where they received 300 mg or 200 mg niraparib tablets or capsules for once daily dosing depending on their body weight and platelet count. | 15 |
| Stage 1: Niraparib Capsule/Tablet Participants received a single oral dose of 3x100 mg niraparib capsules in a fasted state in Period 1, followed by a wash-out period of 7 days. In Period 2, participants received a single oral dose of 300 mg niraparib tablet in a fasted state followed by a 7-day wash-out period. After the last dose of niraparib, participants who did not enter the Extension Phase were followed for up to 30 days (safety f/u) while participants eligible for Extension Phase proceeded for Extension Phase screening. Eligible participants then entered the Extension Phase, where they received 300 mg or 200 mg niraparib tablets or capsules for once daily dosing depending on their body weight and platelet count. | 14 |
| Stage 2: Niraparib Tablet/Capsule Participants received a single oral dose of 300 mg niraparib tablet in a fasted state in Period 1, followed by a wash-out period of 14 days. In Period 2, participants received a single oral dose of 3 capsules of 100 mg niraparib in a fasted state followed by a 7-day wash-out period. After the last dose of niraparib, participants who did not enter the Extension Phase were followed for up to 30 days (safety f/u) while participants eligible for Extension Phase proceeded for Extension Phase screening. Eligible participants then entered the Extension Phase, where they received 300 mg or 200 mg niraparib tablets or capsules for once daily dosing depending on their body weight and platelet count. | 85 |
| Stage 2: Niraparib Capsule/Tablet Participants received a single oral dose of three 100 mg niraparib capsules in a fasted state in Period 1, followed by a wash-out period of 14 days. In Period 2, participants received a single oral dose of 300 mg niraparib tablet in a fasted state followed by a 7-day wash-out period. After the last dose of niraparib, participants who did not enter the Extension Phase were followed for up to 30 days (safety f/u) while participants eligible for Extension Phase proceeded for Extension Phase screening. Eligible participants then entered the Extension Phase, where they received 300 mg or 200 mg niraparib tablets or capsules for once daily dosing depending on their body weight and platelet count. | 83 |
| Stage 3: Niraparib Tablet Fasted/Fed Participants received a single oral dose of 300 mg niraparib tablet in a fasted state in Period 1, followed by a wash-out period of 14 days. In period 2, participants received a single oral dose of 300 mg niraparib tablet in a fed state with a high fat meal followed by a 7-day wash-out period. After the last dose of niraparib, participants who did not enter the Extension Phase were followed for up to 30 days (safety f/u) while participants eligible for Extension Phase proceeded for Extension Phase screening. Eligible participants then entered the Extension Phase, where they received 300 mg or 200 mg niraparib tablets or capsules for once daily dosing depending on their body weight and platelet count. | 14 |
| Stage 3: Niraparib Tablet Fed/Fasted Participants received a single oral dose of 300 mg niraparib tablet in a fed state with a high fat meal in Period 1, followed by a wash-out period of 14 days. In period 2, participants received a single oral dose of 300 mg niraparib tablet in a fasted state followed by a 7-day wash-out period. After the last dose of niraparib, participants who did not enter the Extension Phase were followed for up to 30 days (safety f/u) while participants eligible for Extension Phase proceeded for Extension Phase screening. Eligible participants then entered the Extension Phase, where they received 300 mg or 200 mg niraparib tablets or capsules for once daily dosing depending on their body weight and platelet count. | 14 |
| Total | 225 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 | FG005 | FG006 | FG007 |
|---|---|---|---|---|---|---|---|---|---|
| Extension Phase(Approx 5 Years 5 Months) | Death | 0 | 0 | 0 | 0 | 0 | 0 | 15 | 3 |
| Extension Phase(Approx 5 Years 5 Months) | Lost to Follow-up | 0 | 0 | 0 | 0 | 0 | 0 | 4 | 0 |
| Extension Phase(Approx 5 Years 5 Months) | Other reasons | 0 | 0 | 0 | 0 | 0 | 0 | 30 | 13 |
| Extension Phase(Approx 5 Years 5 Months) | Withdrawal by Subject | 0 | 0 | 0 | 0 | 0 | 0 | 22 | 14 |
| Stage 2: PK Phase-Period 1 (Day 1) | Randomized, but did not receive treatment | 0 | 0 | 5 | 6 | 0 | 0 | 0 | 0 |
| Stage 2: PK Phase-W1 (Up to Day 14) | Adverse Event | 0 | 0 | 5 | 2 | 0 | 0 | 0 | 0 |
| Stage 2: PK Phase-W1 (Up to Day 14) | Death | 0 | 0 | 1 | 2 | 0 | 0 | 0 | 0 |
| Stage 2: PK Phase-W1 (Up to Day 14) | Deemed unevaluable | 0 | 0 | 0 | 1 | 0 | 0 | 0 | 0 |
| Stage 2: PK Phase-W1 (Up to Day 14) | Disease progression per Investigator Decision | 0 | 0 | 3 | 3 | 0 | 0 | 0 | 0 |
| Stage 2: PK Phase-W1 (Up to Day 14) | Participant admitted to emergency room for elevated serum creatinine | 0 | 0 | 1 | 0 | 0 | 0 | 0 | 0 |
| Stage 2: PK Phase-W1 (Up to Day 14) | Participant had incorrectly overdosed and removed from PK phase | 0 | 0 | 1 | 0 | 0 | 0 | 0 | 0 |
| Stage 2: PK Phase-W1 (Up to Day 14) | Participant non-compliance | 0 | 0 | 1 | 0 | 0 | 0 | 0 | 0 |
| Stage 2: PK Phase-W1 (Up to Day 14) | Participant unable to complete due to Tornado in site area | 0 | 0 | 1 | 0 | 0 | 0 | 0 | 0 |
| Stage 2: PK Phase-W1 (Up to Day 14) | Protocol Violation | 0 | 0 | 1 | 0 | 0 | 0 | 0 | 0 |
| Stage 2: PK Phase-W1 (Up to Day 14) | Sponsor and Investigator decision | 0 | 0 | 0 | 1 | 0 | 0 | 0 | 0 |
| Stage 2: PK Phase-W1 (Up to Day 14) | Sponsor discontinued the participant | 0 | 0 | 0 | 1 | 0 | 0 | 0 | 0 |
| Stage 2: PK Phase-W1 (Up to Day 14) | Vomiting within protocol-specified hours of dose administration | 0 | 0 | 2 | 2 | 0 | 0 | 0 | 0 |
| Stage2:PK Phase W2 (Up to Day 7) | Adverse Event | 0 | 0 | 0 | 2 | 0 | 0 | 0 | 0 |
| Stage2:PK Phase W2 (Up to Day 7) | Deemed unevaluable | 0 | 0 | 1 | 1 | 0 | 0 | 0 | 0 |
| Stage2:PK Phase W2 (Up to Day 7) | Disease progression per Investigator Decision | 0 | 0 | 2 | 0 | 0 | 0 | 0 | 0 |
| Stage2:PK Phase W2 (Up to Day 7) | Participant forgot appointment | 0 | 0 | 0 | 1 | 0 | 0 | 0 | 0 |
| Stage2:PK Phase W2 (Up to Day 7) | Participant had paracentesis | 0 | 0 | 0 | 1 | 0 | 0 | 0 | 0 |
| Stage2:PK Phase W2 (Up to Day 7) | Participant missed PK sampling in Period 1 Day 8 | 0 | 0 | 1 | 0 | 0 | 0 | 0 | 0 |
| Stage2:PK Phase W2 (Up to Day 7) | Participant was not in fasted state and therefore was outside of protocol compliance | 0 | 0 | 1 | 0 | 0 | 0 | 0 | 0 |
| Stage 3: PK Phase- Period 1 (Day 1) | Adverse Event | 0 | 0 | 0 | 0 | 0 | 1 | 0 | 0 |
| Stage 3: PK Phase- Period 1 (Day 1) | Clinical progression | 0 | 0 | 0 | 0 | 1 | 0 | 0 | 0 |
| Stage 3: PK Phase- Period 1 (Day 1) | Progressive Disease | 0 | 0 | 0 | 0 | 1 | 0 | 0 | 0 |
| Stage 3: PK Phase- Period 1 (Day 1) | Withdrawal by Subject | 0 | 0 | 0 | 0 | 1 | 1 | 0 | 0 |
| Stage 3: PK Phase- Period 2 (Day 15) | Vomiting within protocol-specified hours of dose administration | 0 | 0 | 0 | 0 | 1 | 1 | 0 | 0 |
Baseline characteristics
| Characteristic | Total | Stage 1: Niraparib Tablet/Capsule | Stage 1: Niraparib Capsule/Tablet | Stage 2: Niraparib Tablet/Capsule | Stage 2: Niraparib Capsule/Tablet | Stage 3: Niraparib Tablet Fasted/Fed | Stage 3: Niraparib Tablet Fed/Fasted |
|---|---|---|---|---|---|---|---|
| Age, Customized <18 to <65 years | 108 Participants | 5 Participants | 7 Participants | 43 Participants | 38 Participants | 6 Participants | 9 Participants |
| Age, Customized >=65 to <75 years | 80 Participants | 9 Participants | 4 Participants | 27 Participants | 32 Participants | 7 Participants | 1 Participants |
| Age, Customized >=75 years | 37 Participants | 1 Participants | 3 Participants | 15 Participants | 13 Participants | 1 Participants | 4 Participants |
| Race/Ethnicity, Customized African American | 28 Participants | 1 Participants | 0 Participants | 11 Participants | 11 Participants | 5 Participants | 0 Participants |
| Race/Ethnicity, Customized American Indian or Alaska Native | 2 Participants | 0 Participants | 0 Participants | 2 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race/Ethnicity, Customized Asian | 8 Participants | 0 Participants | 0 Participants | 5 Participants | 3 Participants | 0 Participants | 0 Participants |
| Race/Ethnicity, Customized Unknown | 16 Participants | 0 Participants | 0 Participants | 4 Participants | 7 Participants | 1 Participants | 4 Participants |
| Race/Ethnicity, Customized White | 171 Participants | 14 Participants | 14 Participants | 63 Participants | 62 Participants | 8 Participants | 10 Participants |
| Sex: Female, Male Female | 125 Participants | 9 Participants | 9 Participants | 48 Participants | 48 Participants | 5 Participants | 6 Participants |
| Sex: Female, Male Male | 100 Participants | 6 Participants | 5 Participants | 37 Participants | 35 Participants | 9 Participants | 8 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk | EG005 affected / at risk | EG006 affected / at risk | EG007 affected / at risk |
|---|---|---|---|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 29 | 0 / 29 | 2 / 156 | 5 / 152 | 2 / 26 | 0 / 25 | 15 / 124 | 3 / 66 |
| other Total, other adverse events | 2 / 29 | 7 / 29 | 49 / 156 | 37 / 152 | 6 / 26 | 5 / 25 | 113 / 124 | 64 / 66 |
| serious Total, serious adverse events | 0 / 29 | 0 / 29 | 10 / 156 | 10 / 152 | 4 / 26 | 2 / 25 | 40 / 124 | 20 / 66 |
Outcome results
Primary
Apparent Terminal Volume of Distribution (Vz/F) for Niraparib-Stage 1 PK Phase
Blood samples were collected at indicated time points for pharmacokinetic assessment of Vz/F. Pharmacokinetic parameters were calculated using standard non-compartmental analysis.
Time frame: Pre-dose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24, 48, 72, 96, 120 and 168 hours post-dose in each treatment period
Population: BA Evaluable Population
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Stage 1: Niraparib Tablet | Apparent Terminal Volume of Distribution (Vz/F) for Niraparib-Stage 1 PK Phase | 1260 Liters | Geometric Coefficient of Variation 45.4 |
| Stage 1: Niraparib Capsule | Apparent Terminal Volume of Distribution (Vz/F) for Niraparib-Stage 1 PK Phase | 1100 Liters | Geometric Coefficient of Variation 43.1 |
Primary
Apparent Total Body Clearance (CL/F) for Niraparib-Stage 1 PK Phase
Blood samples were collected at indicated time points for pharmacokinetic assessment of CL/F. Pharmacokinetic parameters were calculated using standard non-compartmental analysis.
Time frame: Pre-dose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24, 48, 72, 96, 120 and 168 hours post-dose in each treatment period
Population: BA Evaluable Population
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Stage 1: Niraparib Tablet | Apparent Total Body Clearance (CL/F) for Niraparib-Stage 1 PK Phase | 18.5 Liters per hour | Geometric Coefficient of Variation 44.5 |
| Stage 1: Niraparib Capsule | Apparent Total Body Clearance (CL/F) for Niraparib-Stage 1 PK Phase | 17.4 Liters per hour | Geometric Coefficient of Variation 41.8 |
Primary
Area Under the Concentration-time Curve From Time 0 Extrapolated to Infinity (AUC[0 to Inf]) for Niraparib-Stage 1 PK Phase
Blood samples were collected at indicated time points for pharmacokinetic assessment of AUC(0 to inf). Pharmacokinetic parameters were calculated using standard non-compartmental analysis.
Time frame: Pre-dose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24, 48, 72, 96, 120 and 168 hours post-dose in each treatment period
Population: BA Evaluable Population
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Stage 1: Niraparib Tablet | Area Under the Concentration-time Curve From Time 0 Extrapolated to Infinity (AUC[0 to Inf]) for Niraparib-Stage 1 PK Phase | 16200 Hours*nanogram per milliliter | Geometric Coefficient of Variation 44.5 |
| Stage 1: Niraparib Capsule | Area Under the Concentration-time Curve From Time 0 Extrapolated to Infinity (AUC[0 to Inf]) for Niraparib-Stage 1 PK Phase | 17200 Hours*nanogram per milliliter | Geometric Coefficient of Variation 41.8 |
90% CI: [0.8631, 0.9841]
Primary
Area Under the Concentration-time Curve From Time 0 to the Time of the Last Quantifiable Concentration (AUC[0-t]) for Niraparib-Stage 1 PK Phase
Blood samples were collected at indicated time points for pharmacokinetic assessment of AUC(0-t). Pharmacokinetic parameters were calculated using standard non-compartmental analysis.
Time frame: Pre-dose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24, 48, 72, 96, 120 and 168 hours post-dose in each treatment period
Population: Bioavailability (BA) Evaluable Population included all participants who completed both PK Periods and had sufficient PK sample collection to accurately estimate PK parameters, without significant niraparib carryover (Baseline concentration \>5 percent (%) of maximum observed plasma concentration \[Cmax\]), in both Periods.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Stage 1: Niraparib Tablet | Area Under the Concentration-time Curve From Time 0 to the Time of the Last Quantifiable Concentration (AUC[0-t]) for Niraparib-Stage 1 PK Phase | 14900 Hours*nanogram per milliliter | Geometric Coefficient of Variation 43 |
| Stage 1: Niraparib Capsule | Area Under the Concentration-time Curve From Time 0 to the Time of the Last Quantifiable Concentration (AUC[0-t]) for Niraparib-Stage 1 PK Phase | 16100 Hours*nanogram per milliliter | Geometric Coefficient of Variation 41.3 |
90% CI: [0.855, 0.9706]
Primary
AUC(0-t) for Niraparib-Stage 2 PK Phase
Blood samples were collected at indicated time points for pharmacokinetic assessment of AUC(0-t). Pharmacokinetic parameters were calculated using standard non-compartmental analysis.
Time frame: Pre-dose, 1, 1.5, 2, 3, 4, 5, 6, 7, 8, 12, 24, 48, 72, 96, 120 and 168 hours post-dose in each treatment period
Population: Bioequivalence (BE) Evaluable Population included all participants who completed both the Study Drug and Washout/PK and had sufficient PK sample collection to accurately estimate PK parameters, without significant niraparib carryover and without events or protocol deviations deemed affect PK, in both Periods. Only those participants with estimable PK parameter data in both periods were analyzed.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Stage 1: Niraparib Tablet | AUC(0-t) for Niraparib-Stage 2 PK Phase | 17070 Hours*nanogram per milliliter | Geometric Coefficient of Variation 57.1 |
| Stage 1: Niraparib Capsule | AUC(0-t) for Niraparib-Stage 2 PK Phase | 17730 Hours*nanogram per milliliter | Geometric Coefficient of Variation 54.1 |
90% CI: [0.9199, 1.0006]
Primary
AUC(0-t) for Niraparib-Stage 3 PK Phase
Blood samples were collected at indicated time points for pharmacokinetic assessment of AUC(0-t). Pharmacokinetic parameters were calculated using standard non-compartmental analysis.
Time frame: Pre-dose, 1, 1.5, 2, 3, 4, 5, 6, 7, 8, 12, 24, 48, 72, 96, 120 and 168 hours post-dose in each treatment period
Population: Food Effect (FE) Evaluable Population included all participants who completed both PK periods and had sufficient PK sample collection to accurately estimate PK parameters in both periods. Participants meeting non-evaluability criteria or having significant niraparib carryover (Baseline concentration \>5% of Cmax) were completely excluded from the FE Population. Only those participants with estimable PK parameter data available in both Periods were analyzed.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Stage 1: Niraparib Tablet | AUC(0-t) for Niraparib-Stage 3 PK Phase | 20100 Hours*nanogram per milliliter | Geometric Coefficient of Variation 63.9 |
| Stage 1: Niraparib Capsule | AUC(0-t) for Niraparib-Stage 3 PK Phase | 25990 Hours*nanogram per milliliter | Geometric Coefficient of Variation 52.4 |
90% CI: [1.1742, 1.4735]
Primary
AUC(0 to Inf) for Niraparib-Stage 2 PK Phase
Blood samples were collected at indicated time points for pharmacokinetic assessment of AUC(0 to inf). Pharmacokinetic parameters were calculated using standard non-compartmental analysis.
Time frame: Pre-dose, 1, 1.5, 2, 3, 4, 5, 6, 7, 8, 12, 24, 48, 72, 96, 120 and 168 hours post-dose in each treatment period
Population: BE Evaluable Population. Only those participants with estimable PK parameter data available in both Periods were analyzed.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Stage 1: Niraparib Tablet | AUC(0 to Inf) for Niraparib-Stage 2 PK Phase | 17760 Hours*nanogram per milliliter | Geometric Coefficient of Variation 55.3 |
| Stage 1: Niraparib Capsule | AUC(0 to Inf) for Niraparib-Stage 2 PK Phase | 18470 Hours*nanogram per milliliter | Geometric Coefficient of Variation 53.5 |
90% CI: [0.9164, 0.9986]
Primary
AUC(0 to Inf) for Niraparib-Stage 3 PK Phase
Blood samples were collected at indicated time points for pharmacokinetic assessment of AUC(0 to inf). Pharmacokinetic parameters were calculated using standard non-compartmental analysis.
Time frame: Pre-dose, 1, 1.5, 2, 3, 4, 5, 6, 7, 8, 12, 24, 48, 72, 96, 120 and 168 hours post-dose in each treatment period
Population: FE Evaluable Population. Only those participants with estimable PK parameter data available in both Periods were analyzed.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Stage 1: Niraparib Tablet | AUC(0 to Inf) for Niraparib-Stage 3 PK Phase | 23600 Hours*nanogram per milliliter | Geometric Coefficient of Variation 78.5 |
| Stage 1: Niraparib Capsule | AUC(0 to Inf) for Niraparib-Stage 3 PK Phase | 29770 Hours*nanogram per milliliter | Geometric Coefficient of Variation 65.2 |
90% CI: [1.1537, 1.4137]
Primary
CL/F for Niraparib-Stage 2 PK Phase
Blood samples were collected at indicated time points for pharmacokinetic assessment of CL/F. Pharmacokinetic parameters were calculated using standard non-compartmental analysis.
Time frame: Pre-dose, 1, 1.5, 2, 3, 4, 5, 6, 7, 8, 12, 24, 48, 72, 96, 120 and 168 hours post-dose in each treatment period
Population: BE Evaluable Population. Only those participants with estimable PK parameter data available in both Periods were analyzed.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Stage 1: Niraparib Tablet | CL/F for Niraparib-Stage 2 PK Phase | 16.89 Liters per hour | Geometric Coefficient of Variation 55.3 |
| Stage 1: Niraparib Capsule | CL/F for Niraparib-Stage 2 PK Phase | 16.25 Liters per hour | Geometric Coefficient of Variation 53.5 |
Primary
CL/F for Niraparib-Stage 3 PK Phase
Blood samples were collected at indicated time points for pharmacokinetic assessment of CL/F. Pharmacokinetic parameters were calculated using standard non-compartmental analysis.
Time frame: Pre-dose, 1, 1.5, 2, 3, 4, 5, 6, 7, 8, 12, 24, 48, 72, 96, 120 and 168 hours post-dose in each treatment period
Population: FE Evaluable Population. Only those participants with estimable PK parameter data available in both Periods were analyzed.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Stage 1: Niraparib Tablet | CL/F for Niraparib-Stage 3 PK Phase | 12.71 Liters per hour | Geometric Coefficient of Variation 78.5 |
| Stage 1: Niraparib Capsule | CL/F for Niraparib-Stage 3 PK Phase | 10.08 Liters per hour | Geometric Coefficient of Variation 65.2 |
Primary
Cmax for Niraparib-Stage 2 PK Phase
Blood samples were collected at indicated time points for pharmacokinetic assessment of Cmax. Pharmacokinetic parameters were calculated using standard non-compartmental analysis.
Time frame: Pre-dose, 1, 1.5, 2, 3, 4, 5, 6, 7, 8, 12, 24, 48, 72, 96, 120 and 168 hours post-dose in each treatment period
Population: BE Evaluable Population
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Stage 1: Niraparib Tablet | Cmax for Niraparib-Stage 2 PK Phase | 519.5 Nanograms per milliliter | Geometric Coefficient of Variation 49.5 |
| Stage 1: Niraparib Capsule | Cmax for Niraparib-Stage 2 PK Phase | 538.4 Nanograms per milliliter | Geometric Coefficient of Variation 49.4 |
90% CI: [0.9124, 1.014]
Primary
Cmax for Niraparib-Stage 3 PK Phase
Blood samples were collected at indicated time points for pharmacokinetic assessment of Cmax. Pharmacokinetic parameters were calculated using standard non-compartmental analysis.
Time frame: Pre-dose, 1, 1.5, 2, 3, 4, 5, 6, 7, 8, 12, 24, 48, 72, 96, 120 and 168 hours post-dose in each treatment period
Population: FE Evaluable Population.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Stage 1: Niraparib Tablet | Cmax for Niraparib-Stage 3 PK Phase | 704.1 Nanograms per milliliter | Geometric Coefficient of Variation 57 |
| Stage 1: Niraparib Capsule | Cmax for Niraparib-Stage 3 PK Phase | 774.6 Nanograms per milliliter | Geometric Coefficient of Variation 47.2 |
90% CI: [0.9408, 1.3164]
Primary
Maximum Observed Plasma Concentration (Cmax) for Niraparib-Stage 1 PK Phase
Blood samples were collected at indicated time points for pharmacokinetic assessment of Cmax. Pharmacokinetic parameters were calculated using standard non-compartmental analysis.
Time frame: Pre-dose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24, 48, 72, 96, 120 and 168 hours post-dose in each treatment period
Population: BA Evaluable Population
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Stage 1: Niraparib Tablet | Maximum Observed Plasma Concentration (Cmax) for Niraparib-Stage 1 PK Phase | 451 Nanograms per milliliter | Geometric Coefficient of Variation 47.8 |
| Stage 1: Niraparib Capsule | Maximum Observed Plasma Concentration (Cmax) for Niraparib-Stage 1 PK Phase | 467 Nanograms per milliliter | Geometric Coefficient of Variation 50 |
90% CI: [0.8489, 1.0593]
Primary
T1/2 for Niraparib-Stage 2 PK Phase
Blood samples were collected at indicated time points for pharmacokinetic assessment of T1/2. Pharmacokinetic parameters were calculated using standard non-compartmental analysis.
Time frame: Pre-dose, 1, 1.5, 2, 3, 4, 5, 6, 7, 8, 12, 24, 48, 72, 96, 120 and 168 hours post-dose in each treatment period
Population: BE Evaluable Population
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Stage 1: Niraparib Tablet | T1/2 for Niraparib-Stage 2 PK Phase | 47.94 Hours | Geometric Coefficient of Variation 26.4 |
| Stage 1: Niraparib Capsule | T1/2 for Niraparib-Stage 2 PK Phase | 50.17 Hours | Geometric Coefficient of Variation 26.1 |
Primary
T1/2 for Niraparib-Stage 3 PK Phase
Blood samples were collected at indicated time points for pharmacokinetic assessment of T1/2. Pharmacokinetic parameters were calculated using standard non-compartmental analysis.
Time frame: Pre-dose, 1, 1.5, 2, 3, 4, 5, 6, 7, 8, 12, 24, 48, 72, 96, 120 and 168 hours post-dose in each treatment period
Population: FE Evaluable Population.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Stage 1: Niraparib Tablet | T1/2 for Niraparib-Stage 3 PK Phase | 46.39 Hours | Geometric Coefficient of Variation 20.5 |
| Stage 1: Niraparib Capsule | T1/2 for Niraparib-Stage 3 PK Phase | 46.08 Hours | Geometric Coefficient of Variation 22.4 |
Primary
Terminal Half-life (T1/2) for Niraparib-Stage 1 PK Phase
Blood samples were collected at indicated time points for pharmacokinetic assessment of T1/2. Pharmacokinetic parameters were calculated using standard non-compartmental analysis.
Time frame: Pre-dose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24, 48, 72, 96, 120 and 168 hours post-dose in each treatment period
Population: BA Evaluable Population
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Stage 1: Niraparib Tablet | Terminal Half-life (T1/2) for Niraparib-Stage 1 PK Phase | 47.3 Hours | Geometric Coefficient of Variation 22.2 |
| Stage 1: Niraparib Capsule | Terminal Half-life (T1/2) for Niraparib-Stage 1 PK Phase | 43.8 Hours | Geometric Coefficient of Variation 23.1 |
Primary
Time From Administration of the Dose to the First Quantifiable Concentration (Tlag) for Niraparib-Stage 3 PK Phase
Blood samples were collected at indicated time points for pharmacokinetic assessment of tlag. Pharmacokinetic parameters were calculated using standard non-compartmental analysis.
Time frame: Pre-dose, 1, 1.5, 2, 3, 4, 5, 6, 7, 8, 12, 24, 48, 72, 96, 120 and 168 hours post-dose in each treatment period
Population: FE Evaluable Population.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Stage 1: Niraparib Tablet | Time From Administration of the Dose to the First Quantifiable Concentration (Tlag) for Niraparib-Stage 3 PK Phase | 0.00 Hours |
| Stage 1: Niraparib Capsule | Time From Administration of the Dose to the First Quantifiable Concentration (Tlag) for Niraparib-Stage 3 PK Phase | 0.00 Hours |
Primary
Time to Reach Maximum Observed Plasma Concentration (Tmax) for Niraparib-Stage 1 PK Phase
Blood samples were collected at indicated time points for pharmacokinetic assessment of Tmax. Pharmacokinetic parameters were calculated using standard non-compartmental analysis.
Time frame: Pre-dose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24, 48, 72, 96, 120 and 168 hours post-dose in each treatment period
Population: BA Evaluable Population
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Stage 1: Niraparib Tablet | Time to Reach Maximum Observed Plasma Concentration (Tmax) for Niraparib-Stage 1 PK Phase | 4.05 Hours |
| Stage 1: Niraparib Capsule | Time to Reach Maximum Observed Plasma Concentration (Tmax) for Niraparib-Stage 1 PK Phase | 4.00 Hours |
Primary
Tmax for Niraparib-Stage 2 PK Phase
Blood samples were collected at indicated time points for pharmacokinetic assessment of Tmax. Pharmacokinetic parameters were calculated using standard non-compartmental analysis.
Time frame: Pre-dose, 1, 1.5, 2, 3, 4, 5, 6, 7, 8, 12, 24, 48, 72, 96, 120 and 168 hours post-dose in each treatment period
Population: BE Evaluable Population
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Stage 1: Niraparib Tablet | Tmax for Niraparib-Stage 2 PK Phase | 5.00 Hours |
| Stage 1: Niraparib Capsule | Tmax for Niraparib-Stage 2 PK Phase | 4.97 Hours |
Primary
Tmax for Niraparib-Stage 3 PK Phase
Blood samples were collected at indicated time points for pharmacokinetic assessment of Tmax. Pharmacokinetic parameters were calculated using standard non-compartmental analysis.
Time frame: Pre-dose, 1, 1.5, 2, 3, 4, 5, 6, 7, 8, 12, 24, 48, 72, 96, 120 and 168 hours post-dose in each treatment period
Population: FE Evaluable Population.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Stage 1: Niraparib Tablet | Tmax for Niraparib-Stage 3 PK Phase | 4.88 Hours |
| Stage 1: Niraparib Capsule | Tmax for Niraparib-Stage 3 PK Phase | 5.97 Hours |
Primary
Vz/F for Niraparib-Stage 2 PK Phase
Blood samples were collected at indicated time points for pharmacokinetic assessment of Vz/F. Pharmacokinetic parameters were calculated using standard non-compartmental analysis.
Time frame: Pre-dose, 1, 1.5, 2, 3, 4, 5, 6, 7, 8, 12, 24, 48, 72, 96, 120 and 168 hours post-dose in each treatment period
Population: BE Evaluable Population. Only those participants with estimable PK parameter data available in both Periods were analyzed.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Stage 1: Niraparib Tablet | Vz/F for Niraparib-Stage 2 PK Phase | 1128 Liters | Geometric Coefficient of Variation 51.1 |
| Stage 1: Niraparib Capsule | Vz/F for Niraparib-Stage 2 PK Phase | 1128 Liters | Geometric Coefficient of Variation 50.9 |
Primary
Vz/F for Niraparib-Stage 3 PK Phase
Blood samples were collected at indicated time points for pharmacokinetic assessment of Vz/F. Pharmacokinetic parameters were calculated using standard non-compartmental analysis.
Time frame: Pre-dose, 1, 1.5, 2, 3, 4, 5, 6, 7, 8, 12, 24, 48, 72, 96, 120 and 168 hours post-dose in each treatment period
Population: FE Evaluable Population. Only those participants with estimable PK parameter data available in both Periods were analyzed.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Stage 1: Niraparib Tablet | Vz/F for Niraparib-Stage 3 PK Phase | 833.8 Liters | Geometric Coefficient of Variation 83.5 |
| Stage 1: Niraparib Capsule | Vz/F for Niraparib-Stage 3 PK Phase | 651.4 Liters | Geometric Coefficient of Variation 54.3 |
Secondary
Number of Participants With TEAEs and Serious TEAEs - Extension Phase
An adverse event is any untoward medical occurrence in a clinical investigation participant administered a medicinal product and which does not necessarily have a causal relationship with this treatment. An SAE is any untoward medical occurrence that, at any dose; results in death; is life threatening; requires inpatient hospitalization or prolongation of existing hospitalization; results in persistent or significant disability/incapacity; is a congenital anomaly/birth defect; or is an important medical event. TEAE is any event that was not present prior to the initiation of study treatment or any event already present that worsens in either intensity or frequency following exposure to study treatment. A summary of number of participants with any TEAEs and serious TEAEs is presented. Serious TEAEs are subset of TEAEs. TEAEs were coded using the Medical Dictionary for Regulatory Affairs (MedDRA dictionary).
Time frame: Up to approximately 5 years 5 months
Population: Safety Population comprised of all participants who received any amount of niraparib in the Open-Label Extension Phase of the study.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Stage 1: Niraparib Tablet | Number of Participants With TEAEs and Serious TEAEs - Extension Phase | TEAEs | 120 Participants |
| Stage 1: Niraparib Tablet | Number of Participants With TEAEs and Serious TEAEs - Extension Phase | Serious TEAEs | 40 Participants |
| Stage 1: Niraparib Capsule | Number of Participants With TEAEs and Serious TEAEs - Extension Phase | TEAEs | 65 Participants |
| Stage 1: Niraparib Capsule | Number of Participants With TEAEs and Serious TEAEs - Extension Phase | Serious TEAEs | 20 Participants |
Secondary
Number of Participants With TEAEs and Serious TEAEs-Stage 2 PK Phase (Periods 1 and 2 Only)
An adverse event is any untoward medical occurrence in a clinical investigation participant administered a medicinal product and which does not necessarily have a causal relationship with this treatment. An SAE is any untoward medical occurrence that, at any dose; results in death; is life threatening; requires inpatient hospitalization or prolongation of existing hospitalization; results in persistent or significant disability/incapacity; is a congenital anomaly/birth defect; or is an important medical event. TEAE is any event that was not present prior to the initiation of study treatment or any event already present that worsens in either intensity or frequency following exposure to study treatment. TEAEs reported under Niraparib tablet and Niraparib capsule arms include TEAEs with onset date during the corresponding period (Period 1 or Period 2) in which the participant received niraparib tablet and capsule, respectively.
Time frame: Up to 24 days
Population: Safety Population comprised of all participants who received any amount of niraparib during the Stage 2 PK Phase of the study.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Stage 1: Niraparib Tablet | Number of Participants With TEAEs and Serious TEAEs-Stage 2 PK Phase (Periods 1 and 2 Only) | TEAE | 86 Participants |
| Stage 1: Niraparib Tablet | Number of Participants With TEAEs and Serious TEAEs-Stage 2 PK Phase (Periods 1 and 2 Only) | Serious TEAE | 10 Participants |
| Stage 1: Niraparib Capsule | Number of Participants With TEAEs and Serious TEAEs-Stage 2 PK Phase (Periods 1 and 2 Only) | TEAE | 73 Participants |
| Stage 1: Niraparib Capsule | Number of Participants With TEAEs and Serious TEAEs-Stage 2 PK Phase (Periods 1 and 2 Only) | Serious TEAE | 10 Participants |
Secondary
Number of Participants With TEAEs and Serious TEAEs-Stage 3 PK Phase (Periods 1 and 2 Only)
An adverse event is any untoward medical occurrence in a clinical investigation participant administered a medicinal product and which does not necessarily have a causal relationship with this treatment. An SAE is any untoward medical occurrence that, at any dose; results in death; is life threatening; requires inpatient hospitalization or prolongation of existing hospitalization; results in persistent or significant disability/incapacity; is a congenital anomaly/birth defect; or is an important medical event. TEAE is any event that was not present prior to the initiation of study treatment or any event already present that worsens in either intensity or frequency following exposure to study treatment. TEAEs reported under Niraparib tablets under fasted and fed arms include TEAEs with onset date during the corresponding period (Period 1 or Period 2) in which the participant received niraparib tablet fasted and fed, respectively.
Time frame: Up to 45 days
Population: Safety Population comprised of all participants who received any amount of niraparib during the Stage 3 PK Phase of the study.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Stage 1: Niraparib Tablet | Number of Participants With TEAEs and Serious TEAEs-Stage 3 PK Phase (Periods 1 and 2 Only) | TEAE | 8 Participants |
| Stage 1: Niraparib Tablet | Number of Participants With TEAEs and Serious TEAEs-Stage 3 PK Phase (Periods 1 and 2 Only) | Serious TEAE | 4 Participants |
| Stage 1: Niraparib Capsule | Number of Participants With TEAEs and Serious TEAEs-Stage 3 PK Phase (Periods 1 and 2 Only) | TEAE | 12 Participants |
| Stage 1: Niraparib Capsule | Number of Participants With TEAEs and Serious TEAEs-Stage 3 PK Phase (Periods 1 and 2 Only) | Serious TEAE | 2 Participants |
Secondary
Number of Participants With TEAEs-leading to Discontinuation - Extension Phase
An adverse event is any untoward medical occurrence in a clinical investigation participant administered a medicinal product and which does not necessarily have a causal relationship with this treatment. TEAE is any event that was not present prior to the initiation of study treatment or any event already present that worsens in either intensity or frequency following exposure to study treatment. A summary of number of participants who discontinued due to any TEAEs is presented. TEAEs were coded using the Medical Dictionary for Regulatory Affairs (MedDRA dictionary).
Time frame: Up to approximately 5 years 5 months
Population: Safety Population comprised of all participants who received any amount of niraparib in the Open-Label Extension Phase of the study.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Stage 1: Niraparib Tablet | Number of Participants With TEAEs-leading to Discontinuation - Extension Phase | 8 Participants |
| Stage 1: Niraparib Capsule | Number of Participants With TEAEs-leading to Discontinuation - Extension Phase | 9 Participants |
Secondary
Number of Participants With TEAEs Leading to Discontinuation -Stage 1 PK Phase (Periods 1 and 2 Only)
An adverse event is any untoward medical occurrence in a clinical investigation participant administered a medicinal product and which does not necessarily have a causal relationship with this treatment. TEAE is any event that was not present prior to the initiation of study treatment or any event already present that worsens in either intensity or frequency following exposure to study treatment. Number of participants with TEAEs leading to discontinuation is reported. TEAEs reported under Niraparib tablet and Niraparib capsule arms include TEAEs with onset date during the corresponding period (Period 1 or Period 2) in which the participant received niraparib tablet and capsule, respectively.
Time frame: Up to 16 days
Population: Safety Population comprised of all participants who received any amount of niraparib during the Stage 1 PK Phase of the study.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Stage 1: Niraparib Tablet | Number of Participants With TEAEs Leading to Discontinuation -Stage 1 PK Phase (Periods 1 and 2 Only) | 0 Participants |
| Stage 1: Niraparib Capsule | Number of Participants With TEAEs Leading to Discontinuation -Stage 1 PK Phase (Periods 1 and 2 Only) | 0 Participants |
Secondary
Number of Participants With TEAEs-leading to Discontinuation Stage 2 PK Phase (Periods 1 and 2 Only)
An adverse event is any untoward medical occurrence in a clinical investigation participant administered a medicinal product and which does not necessarily have a causal relationship with this treatment. Number of participants with TEAEs leading to discontinuation is reported. TEAEs reported under Niraparib tablet and Niraparib capsule arms include TEAEs with onset date during the corresponding period (Period 1 or Period 2) in which the participant received niraparib tablet and capsule, respectively.
Time frame: Up to 24 days
Population: Safety Population comprised of all participants who received any amount of niraparib during the Stage 2 PK Phase of the study.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Stage 1: Niraparib Tablet | Number of Participants With TEAEs-leading to Discontinuation Stage 2 PK Phase (Periods 1 and 2 Only) | 2 Participants |
| Stage 1: Niraparib Capsule | Number of Participants With TEAEs-leading to Discontinuation Stage 2 PK Phase (Periods 1 and 2 Only) | 2 Participants |
Secondary
Number of Participants With TEAEs-leading to Discontinuation Stage 3 PK Phase (Periods 1 and 2 Only)
An adverse event is any untoward medical occurrence in a clinical investigation participant administered a medicinal product and which does not necessarily have a causal relationship with this treatment. Number of participants with TEAEs leading to discontinuation is reported. TEAEs reported under Niraparib tablets under fasted and fed arms include TEAEs with onset date during the corresponding period (Period 1 or Period 2) in which the participant received niraparib tablet fasted and fed, respectively.
Time frame: Up to 45 days
Population: Safety Population comprised of all participants who received any amount of niraparib during the Stage 3 PK Phase of the study.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Stage 1: Niraparib Tablet | Number of Participants With TEAEs-leading to Discontinuation Stage 3 PK Phase (Periods 1 and 2 Only) | 1 Participants |
| Stage 1: Niraparib Capsule | Number of Participants With TEAEs-leading to Discontinuation Stage 3 PK Phase (Periods 1 and 2 Only) | 1 Participants |
Secondary
Number of Participants With Treatment Emergent Adverse Events (TEAEs) and Serious TEAEs-Stage 1 PK Phase (Periods 1 and 2 Only)
An adverse event is any untoward medical occurrence in a clinical investigation participant administered a medicinal product and which does not necessarily have a causal relationship with this treatment. A serious adverse event (SAE) is any untoward medical occurrence that, at any dose; results in death; is life threatening; requires inpatient hospitalization or prolongation of existing hospitalization; results in persistent or significant disability/incapacity; is a congenital anomaly/birth defect; or is an important medical event. TEAE is any event that was not present prior to the initiation of study treatment or any event already present that worsens in either intensity or frequency following exposure to study treatment. TEAEs reported under Niraparib tablet and Niraparib capsule arms include TEAEs with onset date during the corresponding period (Period 1 or Period 2) in which the participant received niraparib tablet and capsule, respectively.
Time frame: Up to 16 days
Population: Safety Population comprised of all participants who received any amount of niraparib during the Stage 1 PK Phase of the study.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Stage 1: Niraparib Tablet | Number of Participants With Treatment Emergent Adverse Events (TEAEs) and Serious TEAEs-Stage 1 PK Phase (Periods 1 and 2 Only) | TEAE | 9 Participants |
| Stage 1: Niraparib Tablet | Number of Participants With Treatment Emergent Adverse Events (TEAEs) and Serious TEAEs-Stage 1 PK Phase (Periods 1 and 2 Only) | Serious TEAE | 0 Participants |
| Stage 1: Niraparib Capsule | Number of Participants With Treatment Emergent Adverse Events (TEAEs) and Serious TEAEs-Stage 1 PK Phase (Periods 1 and 2 Only) | TEAE | 12 Participants |
| Stage 1: Niraparib Capsule | Number of Participants With Treatment Emergent Adverse Events (TEAEs) and Serious TEAEs-Stage 1 PK Phase (Periods 1 and 2 Only) | Serious TEAE | 0 Participants |