Effectiveness and Safety of Niraparib as Neoadjuvant Therapy in Advanced Ovarian Cancer With Homologous Recombination Deficiency (NANT): Study Protocol for a Prospective, Multicenter, Exploratory, Phase 2, Single-Arm Study

Abstract

Background: Ovarian cancer (OC) is a heterogeneous gynecological malignancy with a poor prognosis as the majority of patients are diagnosed at an advanced stage. Neoadjuvant chemotherapy (NACT) followed by interval debulking surgery (IDS) is recommended for patients who cannot achieve optimal cytoreduction or cannot endure primary debulking surgery (PDS). As there is an increased risk of chemoresistance for platinum-based NACT, it is important to investigate an alternative option. A Poly (ADP-ribose) polymerase inhibitor (PARPi), niraparib, has shown high anti-tumor activity, especially in homologous recombination deficiency (HRD) positive patients with OC. Thus, niraparib as a neoadjuvant treatment agent may help improve surgery accessibility and create survival benefits.

Methods: This multicenter, prospective, single-arm, open-label, phase II study plans to recruit 53 patients (aged 18-75 years) with newly diagnosed HRD positive, unresectable (Fagotti score ≥ 8 or upper abdominal computed tomography [CT] score ≥ 3) International Federation of Gynecology and Obstetrics (FIGO) stage III-IV OC. The HRD status was detected by next-generation sequencing and HRD positive patients will be counseled for study participation. Enrolled patients will receive niraparib capsules QD (200mg or 300mg per day) for two cycles (4 weeks/cycle). After neoadjuvant niraparib treatment, patients exhibiting complete response (CR), partial response (PR), or stable disease (SD) will undergo tumor reduction surgery and subsequent standard carboplatin/paclitaxel-based chemotherapy. The primary objectives include the objective response rate (ORR) and R0 resection rate. The rate of treatment interruption/termination and progression-free survival (PFS) will be secondary objectives. The study uses Simon's optimal two-stage design (24 and 21 patients for the first and second stage respectively). The data manager will record all adverse events (AEs).

Discussion: This is the first prospective study to evaluate the effectiveness and safety of niraparib in neoadjuvant treatment for advanced OC. The result of this study will provide a solid base for further expanding the clinical applications of the PAPRi and exploring more therapeutic possibilities for patients with HRD positive advanced OC. Clinical Trial Registration: https://ichgcp.net/clinical-trials-registry/NCT04507841" title="See in ClinicalTrials.gov">NCT04507841.

Keywords: HRD; neoadjuvant therapy; niraparib; ovarian cancer; phase II study; single-arm.

Conflict of interest statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Copyright © 2022 Zhou, Liu, Liu, Li, Huang, Ma, Hong and Gao.

Figures

Figure 1

Study Design. *Blood and tissue samples were collected at various stages i.e., before and during treatment, disease progression/recurrence, during surgery and post-operative chemotherapy and follow-up. **CA-125 was determined as per Gynecologic Cancer Intergroup Consensus (GCIC) guidelines. ***Abdominal CT or laparoscopy is recommended to classify objective remission status. CA-125, cancer antigen-125; CR, complete response; CT, computed tomography; FIGO, International Federation of Gynecology and Obstetrics; HRD, homologous recombination deficiency; NACT, neoadjuvant chemotherapy; N, number; PD, progressive disease; PR, partial response; RECIST, Response Evaluation Criteria in Solid Tumors; SD, stable disease; TC, Paclitaxel and carboplatin regimen.

Figure 2

Follow-up plan. 1In addition to the prescribed visit schedule, local researchers may conduct more frequent inspections as per patients’ requirements, which may include blood and urine routine examination, blood biochemistry, ECG, CT, and serum tumor biomarker (within one week); 2Refers to platinum-based chemotherapy post-surgery and included information collected from the patient’s medical record; 3It should not be completed >4 weeks before enrolment, excluding exceptional cases; 4Required to be completed within 72 hours of the start of the cycle 1 ( ± 1D); 5Required to be completed within 72 hours of the start of the cycle 2 ( ± 1D); 6Required to be completed within 72 hours from the beginning of cycle 2 treatment D28 (± 1D); 7Required to be completed within 3 days pre-operation; 8Once every 12 weeks after maintenance treatment and once every 24 weeks after two years; 9Includes name, age, gender, place of origin, contact details and date of admission; 10Time interval from last inspection should be >7 days, otherwise the inspection shall be canceled; 11Includes heart rate, blood pressure, pulse and respiration; 12Records the tumor size at least; 13Recommended, non-mandatory; 14The United States Eastern Cooperative Oncology Group (ECOG) physical status scores; 15Blood or urine β-HCG test; 16Completed within two weeks before enrollment; 17Includes neutrophil/platelet count, and Hb level; 18Atleast 7 days before enrollment; 19Includes measurement of serum creatinine and electrolytes, total bilirubin, ALT/AST; 20Time interval from the last inspection should not be <1 week, otherwise the inspection shall be canceled; 21Includes measurement of creatinine, urea nitrogen, and erythrocytes; 22Includes testing of CA125, CA199, CEA, and HE4 related markers; 23Biopsy done by laparoscopy, laparotomy, or coarse-needle aspiration; 24Primary and metastatic tumor tissues obtained by laparotomy/laparoscopic tumor reduction surgery; 25Samples in 2ml EDTA anticoagulant tube were used for HRD detection before enrollment and after two courses of treatment. Samples of 10ml Streck tube were collected before enrollment, D15 and D28 of the first course of chemotherapy, D15 of the second course of chemotherapy, and before tumor reduction surgery and subsequent therapy; 26Abdominal CT or MRI is recommended for evaluation instead of ultrasound alone; 27If blood routine tests are abnormal during maintenance treatment, then it should be carried out every 3 days and closely monitored until it becomes normal; 28The operation record of the biopsy should be sent to the research center for record within 7 days; 29Surgical records should be completed within 24 hours after the surgery and sent to the research center within 7 days for reference; 30All adverse events to be documented from first day of receiving niraparib to post 30 days of treatment termination; 31All adverse events to be documented from first day of receiving niraparib to post 30 days of treatment termination; 32Postoperative adverse events (D1 to D28); 33Includes FACT-O, HADS, ISI, IPAQ, and EQ-VAS; 34Recurrence and time of recurrence, death and time of death, whether to continue follow-up and last follow-up time are recorded; 35The last follow-up before withdrawal; 36After the completion of first-line chemotherapy, patients will receive maintenance treatment with niraparib within 12 weeks. ALT/AST, alanine aminotransferase/aspartate aminotransferase; CA, cancer antigen; CEA, carcinoembryonic antigen; CT, computed tomography; D, day; ECOG, Eastern Cooperative Oncology Group; ECG, electrocardiogram; EDTA, ethylenediaminetetraacetic acid; EQ-VAS, EuroQol-visual analog scales; FACT-O, Functional Assessment of Cancer Therapy-Ovarian; HADS, Hospital Anxiety and Depression Scale; Hb, hemoglobin; β-HCG, β-human chorionic gonadotropin; HE4, human epididymis protein 4; HRD, homologous recombination deficiency; IPAQ, International Physical Activity Questionnaire; ISI, Insomnia Severity Index; MRI, magnetic resonance imaging.

Figure 3

Sample collection plan. 1In addition to pathological sections, one copy of frozen, paraffin-embedded tissue for gene detection, and RNA preservation samples will be sent for sample retention. Also, samples in 2ml EDTA anticoagulant tube and in 10 ml streck tube should be sent to Tongji laboratory immediately for ctDNA sequencing; 2Tissue sample specimens should first meet the requirements of normal histopathological examination, and the remaining samples should be subjected to gene detection and tissue preservation according to the sample collection process; 3Tissue samples should be obtained at the time of biopsy. Sample in 2ml EDTA anticoagulant tube and in 10 ml streck tube should be sent to Tongji laboratory; 4Blood samples should be obtained within 72 hours after two weeks of the first cycle of treatment; 5Blood samples should be obtained within 72 hours on Day 1, 15 and the last day of the second course of treatment; 6Tissue samples should be obtained intraoperatively and blood samples within 72 hours after operation; 7Blood samples should be obtained once before adjuvant chemotherapy after tumor reduction surgery; 8The third and sixth cycles of chemotherapy were obtained on Day 1; 9During the maintenance treatment of niraparib, follow-up was conducted every 12 weeks to obtain blood samples; 10During the long-term follow-up after the withdrawal of maintenance treatment, follow-up was conducted every 12 weeks, and evaluation was conducted every 24 weeks up to two years to obtain blood samples; 11Tissue samples should be obtained at the time of biopsy, and blood samples should be obtained within one week after confirming recurrence.