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.
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).
