Crossover Study to Assess the Relative Bioavailability and Bioequivalence of Niraparib Tablet Compared to Niraparib Capsule

Phase 1

Completed

Conditions: Neoplasms

Interventions: Drug: Niraparib Tablet
Drug: Niraparib Capsule

Registration Number: NCT03329001

Lead Sponsor: Tesaro, Inc.

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.

Detailed Description: Not available

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 236

Inclusion Criteria

Not provided

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).

Study & Design

Study Type: INTERVENTIONAL

Study Design: CROSSOVER

Arm && Interventions

Group	Intervention	Description
Stage 1: Tablet-Capsule Sequence	Niraparib Capsule	Single dose niraparib tablet followed by single dose niraparib capsule followed by optional daily dosing extension phase
Stage 2: Tablet-Capsule Sequence	Niraparib Tablet	Single dose niraparib tablet followed by single dose niraparib capsule followed by optional daily dosing extension phase.
Stage 1: Tablet-Capsule Sequence	Niraparib Tablet	Single dose niraparib tablet followed by single dose niraparib capsule followed by optional daily dosing extension phase
Stage 1: Capsule-Tablet Sequence	Niraparib Capsule	Single dose niraparib capsule followed by single dose niraparib tablet followed by optional daily dosing extension phase
Stage 2: Capsule-Tablet Sequence	Niraparib Tablet	Single dose niraparib capsule followed by single dose niraparib tablet followed by optional daily dosing extension phase
Stage 1: Capsule-Tablet Sequence	Niraparib Tablet	Single dose niraparib capsule followed by single dose niraparib tablet followed by optional daily dosing extension phase
Stage 2: Tablet-Capsule Sequence	Niraparib Capsule	Single dose niraparib tablet followed by single dose niraparib capsule followed by optional daily dosing extension phase.
Stage 2: Capsule-Tablet Sequence	Niraparib Capsule	Single dose niraparib capsule followed by single dose niraparib tablet followed by optional daily dosing extension phase
Stage 3: High fat meal-fasted sequence	Niraparib Tablet	Single dose niraparib tablet with a high fat meal followed by single dose of niraparib tablet in a fasted state.
Stage 3: Fasted-high fat meal sequence	Niraparib Tablet	Single dose niraparib tablet in a fasted state followed by single dose Niraparib tablet with a high fat meal.

Primary Outcome Measures

Name	Time	Method
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 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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.

Secondary Outcome Measures

Name	Time	Method
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.
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 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 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-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).