Niraparib Rechallenge After Surgery in Ovarian Cancer Patients With Oligometastatic Progression

This is a single-arm phase II clinical trial which will enroll female patients aged ≥ 18 years with high grade serous or endometrioid ovarian cancer (OC) who have had an oligometastatic progression (OMP) during or after the first maintenance therapy with any poly adenosine diphosphate (ADP) ribose polymerase inhibitor (PARPi). OMP is defined as 1-5 metastatic lesions. Patients with systemic metastatic disease are not eligible.

A total of 30 patients with OC and OMP will be enrolled and will receive treatment with niraparib 300 or 200 mg, according to body weight or platelet count. Patients will start treatment within 8 weeks after surgery and will receive it until progressive disease or treatment discontinuation.

The main objective of the study is to evaluate progression-free survival (PFS) of niraparib rechallenge in OC patients with OMP and no residual disease after secondary cytoreductive surgery. Main secondary objectives are to assess the PFS according to biomarker status (BRCAm, BRCAwt, HRD and HRP), the PFS by CA 125, the time to start of first subsequent therapy or death (TFST) and the overall survival (OS).

Inclusion criteria

• Written informed consent form (ICF) prior to beginning specific protocol procedures.
• Female patients ≥ 18 years of age.
• Eastern Cooperative Oncology Group (ECOG) performance status of 0-1.
• Patients must have a life expectancy ≥16 weeks.
• Histologically confirmed high grade serous or endometrioid OC who have an OMP during or after the first maintenance therapy with any PARPi.
• Oligometastatic progression defined as 1-5 lesions (according to European Society for Radiotherapy and Oncology [ESTRO] and American Society for Radiation Oncology [ASTRO] consensus).

Note: Metastatic lymph nodes located within the same anatomical lymph-node chain or station, as confirmed on surgical specimen, shall be counted collectively as one single metastatic lesion.

• Patients must have undergone secondary cytoreductive surgery with centrally confirmed no evidence of macroscopic residual tumor after surgery (complete resection).
• Patients with asymptomatic and treated brain metastases are allowed if:

• Neurosurgical resection ≥ 28 days prior to initiation of study treatment. 2. Not requiring radiotherapy. 3. Not receiving steroid therapy or anticonvulsant for at least 7 days before the first dose of study treatment.

• Documented breast cancer gene 1/2 (BRCA1/2) status and/or homologous recombination (HR) status.

Note I: Patients with germline or somatic mutations in the BRCA1 or BRCA2 genes will be considered with the HR status known and classified as with homologous recombination deficiency (HRD).

Note II: HR test must be performed before C1D1.

• Patients who have received prior PARPi monotherapy or PARPi together with bevacizumab as maintenance treatment.

• Patients should have had benefit of prior PARPi defined by treatment for ≥12 months from initiation of PARPi maintenance until the date of OMP or have experienced tumor progression after treatment completion. Tumor progression must have been confirmed by computed tomography (CT) and/or PET-CT scan.

• If prior treatment was niraparib, no significant toxicity that led to treatment discontinuation.

• Willingness to provide formalin fixed, paraffin embedded (FFPE) tumor tissue from primary, if available, and secondary surgeries and blood samples at the time of the inclusion, every 12 weeks, and at the end of treatment (EoT).

• Able to take oral medications. 15. Patients must start treatment 3 to 8 weeks from surgery, once recovered from surgery.

• Women of childbearing potential who engage in heterosexual intercourse must agree to use institution specified method(s) of contraception and must refrain from donating eggs in the time period specified in the study protocol. Women of childbearing potential must have a negative serum or a highly sensitive urine pregnancy test within 72 hours before study treatment initiation.

• Patient has adequate bone marrow, liver, and renal function:

• Hematological: White blood cell (WBC) count > 3.0 x 109/L, absolute neutrophil count (ANC) ≥ 1.5 x 109/L, platelet count ≥ 100.0 x109/L, and hemoglobin ≥ 9.0 g/dL (≥ 5.6 mmol/L).
• Hepatic: total bilirubin ≤ institutional upper limit of normal (ULN) (except for Gilbert's syndrome); alkaline phosphatase (ALP) ≤ 2.5 times ULN; aspartate transaminase (AST) and alanine transaminase (ALT) ≤ 1.5 times ULN. 11).
• Renal: serum creatinine ≤ 1.5 x ULN or creatinine clearance ≥ 50 mL/min/1.73 m2 for patients with creatinine levels above institutional normal.

• Patients must be accessible for treatment follow-up.

Exclusion criteria

• Patients with symptomatic or systemic progressive disease not fulfilling OMP disease criteria.
• Patients with residual disease after secondary cytoreductive surgery.
• Patients with persistent toxicities (> Common Terminology Criteria for Adverse Events (CTCAE) grade 2) caused by previous cancer therapy.
• Patients unable to swallow oral medication or with any life-threatening illness, medical condition, or organ system dysfunction which, in the investigator's opinion, could compromise the subject's safety, interfere with the absorption or metabolism of niraparib, or put the study outcomes at undue risk.
• Patients with clinically significant cardiovascular disease such as uncontrolled hypertension, uncontrolled or symptomatic arrythmias, congestive heart failure (CHF), or myocardial infarction within 6 months of screening, or any Class 3 (moderate) or Class 4 (severe) cardiac disease as defined by the New York Heart Association (NYHA) Functional Classification.
• Patients treated with previous PARPi therapy who have any known, persistent (>4 weeks), ≥Grade 3 anemia, neutrophil count decrease or platelet count decrease.
• Patients with known history of human immunodeficiency virus (HIV), or active hepatitis C Virus (HCV), or active hepatitis B Virus (HBV) infection, or any uncontrolled active systemic infection requiring intravenous antibiotics.
• Patients with known hypersensitivity or allergy to prior niraparib treatment or any of the excipients of the product.
• Patients who have received a transfusion of platelets or red blood cells, colony-stimulating factors or have any other laboratory abnormality within 2 weeks prior niraparib treatment that might confound or interfere with the study result.
• Participation in another clinical trial, interventional or observational, until the Study's safety visit.

Note: participation in retrospective studies or data analysis is allowed.

• Patients who are pregnant or breastfeeding or expecting to conceive children within the projected duration of the study treatment.
• Patients with myelodysplastic syndrome (MSD)/Acute myeloid leukemia (AML), with history of MSD/AML or with features suggestive of MDS/AML.
• Previous allogenic bone marrow transplant or double umbilical cord blood transplantation (dUCBT).
• Other malignancy unless curatively treated with no evidence of disease ≥ 5 years prior to study enrollment. Note: Patients with adequately non-melanoma skin cancer, curatively treated in situ cancer of the cervix, ductal carcinoma in situ (DCIS) and stage 1 low grade endometrial carcinoma are not excluded.
• Vaccination with any live virus vaccine within 28 days prior study treatment initiation.