Absorption, metabolism, excretion, and the determination of absolute bioavailability of Niraparib in subjects with cancer

Completed

• Conditions: and that may benefit from treatment with a PARP inhibitor; cancer; metastatic or locally advanced solid tumors that have failed to respond to standard therapy; have progressed despite standard therapy; or for which no standard therapy exists; refuse standard therapy; 10027655

• Registration Number: NL-OMON41940
• Lead Sponsor: TESARO, Inc

Brief Summary

Not available

Detailed Description

Not available

Study Timeline

• Last Update Posted: 23 April 2024

Recruitment & Eligibility

• Status: Completed
• Sex: Not specified
• Target Recruitment: 12

Inclusion Criteria

To be considered eligible to participate in this study, all of the following requirements must be
met:
1. Subject is capable of understanding the written informed consent, provides signed and
witnessed written informed consent, and agrees to comply with protocol requirements.
2. Subject, male or female, is at least 18 years of age.
3. Subject has histologically or cytologically confirmed diagnosis of metastatic or locally
advanced solid tumors that have failed to respond to standard therapy, have progressed
despite standard therapy, refuse standard therapy, or for which no standard therapy exists,
and that may benefit from treatment with a poly (adenosine diphosphate [ADP]-ribose) polymerase (PARP) inhibitor. The diagnosis must be
confirmed with a previous computed tomography (CT) scan.
4. The subject has adequate organ function:
a. Absolute neutrophil count >=1500/µL
b. Platelets >=150,000/µL
c. Hemoglobin >=9 g/dL (5.6 mM)
d. Serum creatinine <=1.5 × the upper limit of normal (ULN) or a calculated creatinine
clearance >=60 mL/min using the Cockcroft-Gault equation
e. Total bilirubin <=1.5 × ULN or direct bilirubin <=1 × ULN
f. Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) <=2.5 × ULN unless liver metastases are present, in which case AST
and ALT must be <=5 × ULN
5. Subject must have an ECOG performance status of 0 to 2.
6. Female subjects of childbearing potential must have a negative serum pregnancy test (beta human chorionic gonadotropin [hCG]) within 72 hours prior to receiving the first dose of study drug.
7. Male and female subjects of reproductive potential must use adequate birth control for the
duration of study participation (Section 8.3).
8. Subject is able to take oral medications.
9. Subject must agree to blood samples during screening and at the end of treatment for cytogenetic analysis.

Exclusion Criteria

Subjects will not be eligible for study entry if any of the following criteria are met:
1. Subject has undergone palliative radiotherapy within 1 week of study drug administration, encompassing >20% of the bone marrow.
2. Subject has persistent >Grade 2 toxicity from prior cancer therapy.
3. Subject has any known, persistent (>4 weeks) >=Grade 3 hematological toxicity or fatigue from prior cancer therapy.
4. Subject has symptomatic uncontrolled brain or leptomeningeal metastases. To be considered *controlled,* the subject must have undergone treatment (eg, radiation or chemotherapy at least 1 month prior to study entry) for the central nervous system (CNS) disease. The subject must have no new or progressive signs or symptoms related to the CNS disease and must be taking a stable dose of steroids or no steroids. A scan to confirm the absence of brain metastases is not required. Subjects with spinal cord compression may be considered if they have received definitive treatment and there is evidence of the disease being clinically stable for 28 days.
5. Subject has known hypersensitivity to the components of niraparib.
6. Subject has had major surgery within 3 weeks of study drug administration or has not recovered from all effects of any major surgery.
7. Subject is considered a medical risk due to a serious, uncontrolled medical disorder; nonmalignant systemic disease; or active, uncontrolled infection. Examples include, but are not limited to, uncontrolled ventricular arrhythmia, recent (within 90 days of the Screening Visit) myocardial infarction, uncontrolled major seizure disorder, unstable spinal cord compression, superior vena cava syndrome, or any psychiatric disorder that prohibits obtaining informed consent.
8. Subject received (or is anticipated to receive) a platelet transfusion within 4 weeks of study drug administration.
9. Subject has a history or current evidence of any condition, therapy, or laboratory abnormality (including active or uncontrolled myelosuppresion [ie, anemia, leukopenia, neutropenia,
thrombocytopenia]) that might confound the results of the study, interfere with the subject*s participation for the full duration of the study treatment, or suggests it is not in the best interest of the subject to participate.
10. Subject has any known history of myelodysplastic syndrome (MDS)
or a pre-treatment cytogenetic testing result at risk for a diagnosis of
MDS/acute myeloid leukemia (AML).
11. Subject is pregnant, breastfeeding, or expecting to conceive children within the projected duration of the study treatment.
12. Subject is immunocompromised with an active event and is being treated with medications.
13. Subject has confirmed or suspected hepatitis B virus (HBV), hepatitis C virus (HCV), or human immunodeficiency virus (HIV).
14. Subject has a corrected QT interval (QTc) prolongation of >470 msec at the Screening Visit.
15. Subject is receiving concomitant medication(s) that prolong QTc and is unable to discontinue use for the duration of the study.
16. Subject is starting chemotherapy within 3 weeks of study drug administration.
17. Subject is taking proton pump inhibitors, antacids, or H2 blockers within 48 hours prior to study drug administration, and/or within 6 hours after study drug administration.
18. Subject has a history of illicit drug use.
19. Subject has a past or current history of chronic alcohol use (3 or

Study & Design

• Study Type: Interventional
• Study Design: Not specified

Primary Outcome Measures

Name	Time	Method
<p>The absolute bioavailability of niraparib in subjects with cancer (part 1).<br /><br><br /><br>Plasma niraparib concentrations will be used to determine the following PK<br /><br>parameters: maximum observed plasma concentration (Cmax); time to reach Cmax<br /><br>(Tmax); and area under the plasma concentration-time curve (AUC) from time 0 to<br /><br>the last quantifiable concentration (AUC0-last); and if the data allow: AUC<br /><br>from time 0 to infinity (AUC0-inf); apparent oral volume of distribution<br /><br>(Vd/F); apparent oral clearance (CL/F); and half-life (t*). Absolute<br /><br>bioavailability of niraparib will be calculated as the ratio of dose normalized<br /><br>oral to IV niraparib exposure. </p><br>