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

Neoplasms Clinical Trial

Official title:

An Open-Label, Randomized-Sequence, Multicenter, Single-Crossover Study to Assess the Relative Bioavailability and Bioequivalence of Niraparib Tablet Formulation Compared to Niraparib Capsule Formulation in Patients With Advanced Solid Tumors

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT03329001
• Other study ID #: 213362
• Secondary ID: 3000-01-004
• Status: Completed
• Phase: Phase 1
• Start date: December 4, 2017
• Est. completion date: June 15, 2023

Study information

• Verified date: November 2023
• Source: Tesaro, Inc.
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 236
• Est. completion date: June 15, 2023
• Est. primary completion date: December 30, 2021
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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).

Related Conditions & MeSH terms

• Neoplasms

Intervention

Drug:
• Niraparib Tablet
Niraparib tablet formulation
• Niraparib Capsule
Niraparib capsule formulation

Locations

Country	Name	City	State
United States	GSK Investigational Site	Atlanta	Georgia
United States	GSK Investigational Site	Cincinnati	Ohio
United States	GSK Investigational Site	Cleveland	Ohio
United States	GSK Investigational Site	Dallas	Texas
United States	GSK Investigational Site	Denver	Colorado
United States	GSK Investigational Site	Encinitas	California
United States	GSK Investigational Site	Fresno	California
United States	GSK Investigational Site	Grand Rapids	Michigan
United States	GSK Investigational Site	Houston	Texas
United States	GSK Investigational Site	Jackson	Mississippi
United States	GSK Investigational Site	Nashville	Tennessee
United States	GSK Investigational Site	New Haven	Connecticut
United States	GSK Investigational Site	Oklahoma City	Oklahoma
United States	GSK Investigational Site	San Antonio	Texas
United States	GSK Investigational Site	San Marcos	Texas
United States	GSK Investigational Site	Sarasota	Florida

Sponsors (1)

Lead Sponsor	Collaborator
Tesaro, Inc.

Country where clinical trial is conducted

United States, 

Outcome

Type	Measure	Description	Time frame	Safety issue
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.	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
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.	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
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.	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
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.	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
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.	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
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.	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
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.	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
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.	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
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.	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
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.	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
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.	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
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.	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
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.	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
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.	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
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.	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
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.	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
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.	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
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.	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
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.	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
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.	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
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.	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
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.	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
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.	Up to 16 days
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.	Up to 16 days
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.	Up to 24 days
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.	Up to 24 days
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.	Up to 45 days
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.	Up to 45 days
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. Data is not reported as participants response is still ongoing at the time of primary analysis.	Approximately 1 year
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. Data is not reported as participants response is still ongoing at the time of primary analysis.	Approximately 1 year