Japan Phase 2 Study of Niraparib in Participants With Advanced, Relapsed Ovarian Cancer

The drug being tested in this study is called niraparib. Niraparib is being tested to treat people who have the homologous recombination deficiency (HRD)-positive, advanced, relapsed, high-grade serous epithelial ovarian, fallopian tube, or primary peritoneal cancer. This study will look at the efficacy and safety of niraparib in Japanese participants.

The study will enroll approximately 16 participants. Participants will be enrolled to one group and after that will be asked to take niraparib capsules at the same time each day throughout the study:

\- Niraparib 300 mg

This multi-center trial will be conducted in Japan. The overall time to participate in this study is approximately 23 months. Participants will make multiple visits to the clinic in the treatment period, and the post-treatment period including follow-up assessments after the last dose of the study drug.

• Niraparib (Drug): Niraparib capsule

Primary outcomes

• Objective Response Rate (ORR) [Until disease progression or death (Up to 3.8 years)]: ORR was defined as the percentage of participants achieving CR or PR as assessed by the Investigator per RECIST v.1.1. CR was defined as disappearance of all target lesions and PR was defined as at least a 30% decrease in SoD of target lesions, taking as a reference the Baseline SoD.

Secondary outcomes

• Duration of Response (DOR) [Until disease progression or death (Up to 3.8 years)]: DOR was defined as the time from the first documented CR or PR per RECIST v.1.1 to disease recurrence or objective disease progression whichever occurs first. CR was defined as disappearance of all target lesions and PR was defined as at least a 30% decrease in SoD of target lesions, taking as a reference the Baseline SoD.
• Disease Control Rate (DCR) [Until disease progression or death (Up to 3.8 years)]: DCR was defined as the percentage of participants achieving CR, PR or SD as assessed by the Investigator per RECIST v.1.1. CR was defined as disappearance of all target lesions and PR was defined as at least a 30% decrease in SoD of target lesions, taking as a reference the Baseline SoD. SD was defined as neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD. PD was defined as at least a 20% increase in the SoD of target lesions, taking as a reference the smallest (nadir) SoD since (and including) Baseline.
• Number of Participants With Treatment-Emergent Adverse Events (TEAEs) [From first dose of study drug up to 30 days after the last dose or beginning of subsequent anticancer therapy, whichever came first (Up to 3.8 years)]: An adverse event (AE) was defined as any untoward medical occurrence in a clinical investigation participant administered a drug; it does not necessarily have to have a causal relationship with this treatment. An AE can therefore be any unfavorable and unintended sign (eg, a clinically significant abnormal laboratory finding), symptom, or disease temporally associated with the use of a drug, whether or not it is considered related to the drug. A TEAE was defined as an adverse event with an onset that occurs after receiving study drug.
• Number of Participants With Grade 3 or Higher TEAEs [From first dose of study drug up to 30 days after the last dose or beginning of subsequent anticancer therapy, whichever came first (Up to 3.8 years)]: An AE was defined as any untoward medical occurrence in a participant who has enrolled in a study; it does not necessarily have a causal relationship with this treatment. A TEAE was defined as an adverse event with an onset that occurs after receiving study drug. A severity grade was defined by the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE) Version 4.03. As per NCI-CTCAE, Grade 1 scales as Mild; Grade 2 scales as Moderate; Grade 3 scales as severe or medically significant but not immediately life threatening; Grade 4 scales as life-threatening consequences; and Grade 5 scales as death related to AE.
• Number of Participants With Serious TEAEs [From first dose of study drug up to 30 days after the last dose or beginning of subsequent anticancer therapy, whichever came first (Up to 3.8 years)]: An AE was defined as any untoward medical occurrence in a participant who has enrolled in a study; it does not necessarily have a causal relationship with this treatment. A serious adverse event (SAE) was any AE that results in death, is life-threatening, requires inpatient hospitalization or prolongation of an existing hospitalization, results in significant disability or incapacity, is a congenital anomaly/birth defect or is a medically important event. TEAE was defined as an adverse event with an onset that occurs after receiving study drug.
• Number of Participants With TEAEs Leading to Drug Discontinuation [From first dose of study drug up to 30 days after the last dose or beginning of subsequent anticancer therapy, whichever came first (Up to 3.8 years)]: An AE was defined as any untoward medical occurrence in a participant who has enrolled in a study; it does not necessarily have a causal relationship with this treatment. A TEAE was defined as an adverse event with an onset that occurs after receiving study drug.
• Number of Participants With TEAEs Leading to Dose Interruption [From first dose of study drug up to 30 days after the last dose or beginning of subsequent anticancer therapy, whichever came first (Up to 3.8 years)]: An AE was defined as any untoward medical occurrence in a participant who has enrolled in a study; it does not necessarily have a causal relationship with this treatment. A TEAE was defined as an adverse event with an onset that occurs after receiving study drug.
• Number of Participants With TEAEs Leading to Dose Reduction [From first dose of study drug up to 30 days after the last dose or beginning of subsequent anticancer therapy, whichever came first (Up to 3.8 years)]: An AE was defined as any untoward medical occurrence in a participant who has enrolled in a study; it does not necessarily have a causal relationship with this treatment. A TEAE was defined as an adverse event with an onset that occurs after receiving study drug.
• Progression Free Survival (PFS) [Until disease progression or death (Up to 3.8 years)]: PFS was defined as the time in months from the date of first study drug administration to the date of first documentation of PD or death as assessed by the RECIST v.1.1. Per RECIST 1.1, PD was defined as at least a 20% increase in the SoD of target lesions, taking as a reference the smallest (nadir) SoD since (and including) Baseline.
• Overall Survival (OS) [From first dose of study drug up to 30 days after the last dose or beginning of subsequent anticancer therapy, whichever came first (Up to 3.8 years)]: OS was defined as the time in months from the study enrollment to death due to any cause.

Sex: Female, ages: 20 Years to any

Inclusion Criteria

1. Japanese female participants aged 20 years or older on the day of signing informed consent.
2. Voluntary written consent must be given before performance of any study related procedure not part of standard medical care, with the understanding that consent may be withdrawn by the participant at any time without prejudice to future medical care.
3. Participants must agree to undergo tumor homologous recombination deficiency/deficient (HRD) testing, and this test result must show that participants have an HRD-positive tumor (defined by the presence of a deleterious or suspected deleterious breast cancer gene (BRCA) mutation or be positive for genomic instability) by the central laboratory selected by the sponsor.

   Note 1: The study HRD test result must be received prior to enrollment. The tumor sample may be submitted for HRD testing prior to the screening period (ie, within 40 days before Cycle 1 Day 1) if the consent has been obtained and it appears the participant is likely to meet other eligibility requirements.

   Note 2: If historic blood germline BRCA mutation (gBRCAmut) is detected by a prior gBRCAmut testing, then tumor HRD sample test results are not required prior to enrollment; however, HRD testing still needs to be performed.
4. Participants must have histologically diagnosed, relapsed, high-grade (Grade 2 or 3) serous epithelial ovarian, fallopian tube, or primary peritoneal cancer with recurrent disease and must have been previously treated with chemotherapy and have not experienced disease progression at least 6 months to the last chemotherapy containing platinum-based anticancer agents.
5. Participants must have completed 3 or 4 previous chemotherapy regimens. Participants must have completed their last chemotherapy regimen >4 weeks prior to treatment initiation.
6. Participants must have at least one measurable disease according to Response Evaluation Criteria in Solid Tumors (RECIST) (v.1.1).
7. Participants must have performance status of ≤1 on the Eastern Cooperative Oncology Group (ECOG) Performance Status Scale.
8. Participants must have adequate organ function as indicated by the following laboratory values:

   * Absolute neutrophil count (ANC) ≥1,500/μL.
   * Platelet count ≥150,000/μL.
   * Hemoglobin ≥10 g/dL.
   * Serum creatinine ≤1.5× institutional upper limit of normal (ULN) OR calculated creatinine clearance ≥50 mL/minute, using the Cockcroft-Gault equation.
   * Total bilirubin ≤1.5×ULN OR direct bilirubin ≤1×ULN.
   * Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤2.5×ULN unless liver metastases were present, in which case they had to be ≤5×ULN.
9. Participants must have formalin-fixed, paraffin-embedded tumor samples available from the primary or recurrent cancer or agree to undergo fresh biopsy prior to study treatment initiation.
10. Participants must be able to take oral medications.
11. Female participants of childbearing potential must be negative for pregnancy test (beta-human chorionic gonadotropin \[β-hCG\]) within 7 days prior to receiving the first dose of study treatment.
12. Female participants who:

    * Are postmenopausal for at least 1 year before the screening visit, OR
    * Are surgically sterile, OR
    * If they are of childbearing potential, agree to practice 1 highly effective method of contraception and 1 additional effective (barrier) method at the same time, from the time of signing the informed consent through 180 days after the last dose of study drug, OR
    * Agree to practice true abstinence, when this is in line with the preferred and usual lifestyle of the participant. (Periodic abstinence \[eg, calendar, ovulation, symptothermal, postovulation methods\], condoms only, withdrawal, spermicides only, and lactational amenorrhea are not acceptable methods of contraception. Female and male condoms should not be used together.)

Exclusion Criteria

1. Participants who have had palliative radiotherapy encompassing >20% of the bone marrow within 1 week of the first dose of study treatment.
2. Participants who have any known, persistent (>4 weeks), Grade ≥3 hematologic toxicity from last cancer therapy.
3. Participants who have any known, persistent (>4 weeks), Grade ≥3 fatigue during the last cancer therapy.
4. Participants who have received pelvic radiotherapy as treatment for primary or recurrent disease within 1 year of the first dose of study treatment.
5. Participants who have symptomatic, uncontrolled brain or leptomeningeal metastases.

   To be considered "controlled," central nervous system (CNS) disease must have undergone treatment (eg, radiation or chemotherapy) at least 1 month prior to study enrollment. The participant must not have had any new or progressive signs or symptoms related to the CNS disease and must have been taking a stable dose of steroids or no steroids (as long as these were started at least 4 weeks prior to enrollment\] or no steroids). A scan to confirm the absence of brain metastases at baseline was not required. Participants with spinal cord compression might have been considered if they had received definitive treatment for this and evidence of clinically stable disease for 28 days.
6. Participants who have known hypersensitivity to the components of niraparib.
7. Participants who have had prior treatment with a known poly (adenosine diphosphate \[ADP\]-ribose) polymerase (PARP) inhibitors.
8. Participant who have had treatment with any investigational products within 28 days or 5 half-lives (whichever was longer) before the first dose.
9. Participants who have had major surgery per Investigator judgment within 3 weeks of the first dose. Participant must have recovered from any effects of any major surgery.
10. Participants who have diagnosis, detection, or treatment of invasive second primary malignancy other than ovarian cancer ≤24 months prior to study enrollment (except basal or squamous cell carcinoma of the skin that was definitively treated). Note: Participants must not have any known history or current diagnosis of myelodysplastic syndrome (MDS) or acute myeloid leukemia (AML), irrespective of the time for disease history.
11. Participants who are considered a poor medical risk due to a serious, uncontrolled medical disorder, non-malignant systemic disease, or active, uncontrolled infection. Examples include, but are not limited to, uncontrolled ventricular arrhythmia, recent (within 90 days of the first dose) myocardial infarction, uncontrolled major seizure disorder, unstable spinal cord compression, superior vena cava syndrome, small bowel obstruction or other serious gastrointestinal disorder, or any psychiatric disorder that prohibits obtaining informed consent.
12. Participants who have received a transfusion (platelets or red blood cells) within 4 weeks of the first dose of study treatment.
13. Participants who have received a live virus or bacterial vaccines within 4 weeks of the first dose of study treatment.
14. Participants who have a history or current evidence of any condition, therapy, or lab abnormality (including active or uncontrolled myelosuppression \[ie, anemia, leukopenia, neutropenia, thrombocytopenia\]) that might confound the results of the study, interfere with the participant's participation throughout the study period, or study participation is not in the best interest of the participant.
15. Participants who are regular user (including "recreational use") of any illicit drugs at the time of signing informed consent or have a recent history (within the past year) of drug or alcohol abuse.
16. Participants who are pregnant or breast-feeding or expecting to conceive within the planned duration of the study.

    NOTE: If a breast-feeding woman discontinue breast-feeding, she may be enrolled in the study.
17. Participants who are immunocompromised (participants with splenectomy are allowed).
18. Participants who have known human immunodeficiency virus (HIV) positive.
19. Participants who have known hepatitis B surface antigen (HBsAg) positive, or known or suspected active hepatitis C virus (HCV) infection.

NOTE: Participants who are positive for hepatitis B core antibody (HBcAb) or hepatitis B surface antibody (HBsAb) can be enrolled but must have an undetectable hepatitis B virus (HBV) viral load. Participants who have positive hepatitis C virus antibody (HCVAb) must have an undetectable HCV viral load.

Participant flow

Outcome results

• Objective Response Rate (ORR) (Primary), Number, percentage of participants: Niraparib 300 mg 60.0
• Duration of Response (DOR) (Secondary), Median, months: Niraparib 300 mg 9.9 (3.9 to NA)
• Disease Control Rate (DCR) (Secondary), Number, percentage of participants: Niraparib 300 mg 90.0 (68.302 to 98.765)
• Number of Participants With Treatment-Emergent Adverse Events (TEAEs) (Secondary), Count of participants, Participants: Niraparib 300 mg 20
• Number of Participants With Grade 3 or Higher TEAEs (Secondary), Count of participants, Participants: Niraparib 300 mg 17
• Number of Participants With Serious TEAEs (Secondary), Count of participants, Participants: Niraparib 300 mg 8
• Number of Participants With TEAEs Leading to Drug Discontinuation (Secondary), Count of participants, Participants: Niraparib 300 mg 2
• Number of Participants With TEAEs Leading to Dose Interruption (Secondary), Count of participants, Participants: Niraparib 300 mg 15
• Number of Participants With TEAEs Leading to Dose Reduction (Secondary), Count of participants, Participants: Niraparib 300 mg 16
• Progression Free Survival (PFS) (Secondary), Median, months: Niraparib 300 mg 8.3 (5.6 to 13.8)
• Overall Survival (OS) (Secondary), Median, months: Niraparib 300 mg 24.9 (14.9 to NA)

Adverse events

Time frame: From first dose of study drug up to 30 days after the last dose or beginning of subsequent anticancer therapy, whichever came first (Up to 3.8 years)

Serious adverse events by term

Other adverse events by term

• Results publication: Aoki D, Tabata T, Yanagida S, Nakamura T, Kondo E, Hamanishi J, Harano K, Hasegawa K, Hirasawa T, Hori K, Komiyama S, Matsuura M, Nakai H, Nakamura H, Sakata J, Takehara K, Takekuma M, Yokoyama Y, Kase Y, Sumino S, Soeda J, Kato A, Suri A, Okamoto A, Sugiyama T. Niraparib in Japanese patients with heavily pretreated, homologous recombination-deficient ovarian cancer: final results of a multicenter phase 2 study. J Gynecol Oncol. 2024 Sep;35(5):e114. doi: 10.3802/jgo.2024.35.e114. PMID 39251349
• Results publication: Okamoto A, Kondo E, Nakamura T, Yanagida S, Hamanishi J, Harano K, Hasegawa K, Hirasawa T, Hori K, Komiyama S, Matsuura M, Nakai H, Nakamura H, Sakata J, Tabata T, Takehara K, Takekuma M, Yokoyama Y, Kase Y, Sumino S, Soeda J, Suri A, Aoki D, Sugiyama T. Phase 2 single-arm study on the efficacy and safety of niraparib in Japanese patients with heavily pretreated, homologous recombination-deficient ovarian cancer. J Gynecol Oncol. 2021 Mar;32(2):e16. doi: 10.3802/jgo.2021.32.e16. Epub 2020 Dec 10. PMID 33327047

• Study Protocol (PDF, 2021-11-09)
• Statistical Analysis Plan (PDF, 2019-08-08)

• Medical Director, Study director, Takeda