Clinical trial NCT03329001: Crossover Study to Assess the Relative Bioavailability and Bioequivalence of Niraparib Tablet Compared to Niraparib Capsule
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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
Conditions: Neoplasms
Keywords: PARP inhibitor
niraparib
Solid Tumor
Zejula
Lead sponsor: Tesaro, Inc.
Sponsor class: INDUSTRY
First posted: 2017-11-01
Enrollment: 236
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: CROSSOVER
Primary purpose: TREATMENT

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.


Eligibility 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).

Primary outcomes:
measure: 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
timeFrame: 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
measure: Area Under the Concentration-time Curve From Time 0 Extrapolated to Infinity (AUC[0 to Inf]) for Niraparib-Stage 1 PK Phase
timeFrame: 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
measure: Maximum Observed Plasma Concentration (Cmax) for Niraparib-Stage 1 PK Phase
timeFrame: 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
measure: Time to Reach Maximum Observed Plasma Concentration (Tmax) for Niraparib-Stage 1 PK Phase
timeFrame: 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
measure: Terminal Half-life (T1/2) for Niraparib-Stage 1 PK Phase
timeFrame: 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
measure: Apparent Total Body Clearance (CL/F) for Niraparib-Stage 1 PK Phase
timeFrame: 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
measure: Apparent Terminal Volume of Distribution (Vz/F) for Niraparib-Stage 1 PK Phase
timeFrame: 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
measure: AUC(0-t) for Niraparib-Stage 2 PK Phase
timeFrame: 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
measure: AUC(0 to Inf) for Niraparib-Stage 2 PK Phase
timeFrame: 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
measure: Cmax for Niraparib-Stage 2 PK Phase
timeFrame: 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
measure: Tmax for Niraparib-Stage 2 PK Phase
timeFrame: 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
measure: T1/2 for Niraparib-Stage 2 PK Phase
timeFrame: 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
measure: CL/F for Niraparib-Stage 2 PK Phase
timeFrame: 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
measure: Vz/F for Niraparib-Stage 2 PK Phase
timeFrame: 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
measure: AUC(0-t) for Niraparib-Stage 3 PK Phase
timeFrame: 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
measure: AUC(0 to Inf) for Niraparib-Stage 3 PK Phase
timeFrame: 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
measure: Cmax for Niraparib-Stage 3 PK Phase
timeFrame: 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
measure: Tmax for Niraparib-Stage 3 PK Phase
timeFrame: 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
measure: T1/2 for Niraparib-Stage 3 PK Phase
timeFrame: 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
measure: CL/F for Niraparib-Stage 3 PK Phase
timeFrame: 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
measure: Vz/F for Niraparib-Stage 3 PK Phase
timeFrame: 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
measure: Time From Administration of the Dose to the First Quantifiable Concentration (Tlag) for Niraparib-Stage 3 PK Phase
timeFrame: 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 outcomes:
measure: Number of Participants With Treatment Emergent Adverse Events (TEAEs) and Serious TEAEs-Stage 1 PK Phase (Periods 1 and 2 Only)
timeFrame: Up to 16 days
measure: Number of Participants With TEAEs Leading to Discontinuation -Stage 1 PK Phase (Periods 1 and 2 Only)
timeFrame: Up to 16 days
measure: Number of Participants With TEAEs and Serious TEAEs-Stage 2 PK Phase (Periods 1 and 2 Only)
timeFrame: Up to 24 days
measure: Number of Participants With TEAEs-leading to Discontinuation Stage 2 PK Phase (Periods 1 and 2 Only)
timeFrame: Up to 24 days
measure: Number of Participants With TEAEs and Serious TEAEs-Stage 3 PK Phase (Periods 1 and 2 Only)
timeFrame: Up to 45 days
measure: Number of Participants With TEAEs-leading to Discontinuation Stage 3 PK Phase (Periods 1 and 2 Only)
timeFrame: Up to 45 days
measure: Number of Participants With TEAEs and Serious TEAEs - Extension Phase
timeFrame: Up to approximately 5 years 5 months
measure: Number of Participants With TEAEs-leading to Discontinuation - Extension Phase
timeFrame: Up to approximately 5 years 5 months
Other outcomes:
Locations:
city: Encinitas
country: United States
facility: GSK Investigational Site
state: California
city: Fresno
country: United States
facility: GSK Investigational Site
state: California
city: Denver
country: United States
facility: GSK Investigational Site
state: Colorado
city: New Haven
country: United States
facility: GSK Investigational Site
state: Connecticut
city: Sarasota
country: United States
facility: GSK Investigational Site
state: Florida
city: Atlanta
country: United States
facility: GSK Investigational Site
state: Georgia
city: Grand Rapids
country: United States
facility: GSK Investigational Site
state: Michigan
city: Jackson
country: United States
facility: GSK Investigational Site
state: Mississippi
city: Cincinnati
country: United States
facility: GSK Investigational Site
state: Ohio
city: Cleveland
country: United States
facility: GSK Investigational Site
state: Ohio
city: Oklahoma City
country: United States
facility: GSK Investigational Site
state: Oklahoma
city: Nashville
country: United States
facility: GSK Investigational Site
state: Tennessee
city: Dallas
country: United States
facility: GSK Investigational Site
state: Texas
city: Houston
country: United States
facility: GSK Investigational Site
state: Texas
city: San Antonio
country: United States
facility: GSK Investigational Site
state: Texas
city: San Marcos
country: United States
facility: GSK Investigational Site
state: Texas
Study officials:
affiliation: GlaxoSmithKline
name: GSK Clinical Trials
role: STUDY_DIRECTOR
References:
citation: Falchook G, Patnaik A, Richardson DL, Harvey RD, Sharma MR, Hafez N, Hamilton E, Piha-Paul SA, Barve M, Wise-Draper T, Patel MR, Dowlati A, Pascuzzo J, Tang SC, Faltermeier C, Malinowska IA, Shtessel L, Striha A, Potocka E. A Relative Bioavailability, Bioequivalence, and Food Effect Study of Niraparib Tablets in Patients with Advanced Solid Tumors. Clin Ther. 2024 Mar;46(3):228-238. doi: 10.1016/j.clinthera.2024.01.004. Epub 2024 Feb 28.