Dataset Information

A single-arm, phase II study of niraparib and bevacizumab maintenance therapy in platinum-sensitive, recurrent ovarian cancer patients previously treated with a PARP inhibitor: Korean Gynecologic Oncology Group (KGOG 3056)/NIRVANA-R trial.

ABSTRACT:

Background

Given the expanding clinical use of poly(adenosine diphosphate [ADP]-ribose) polymerase inhibitors (PARPis), there is a significant need for optimal strategies with which to treat patients whose cancer progresses while using a PARPi. However, the treatment consensus after PARPi has not been established. The aim of the Korean Gynecologic Oncology Group (KGOG) 3056/NIRVANA-R trial is to investigate the efficacy of niraparib in combination with bevacizumab as a maintenance therapy in platinum-sensitive ovarian cancer patients who were previously treated with a PARPi.

Methods

The KGOG 3056/NIRVANA-R is a multi-centre, investigator-initiated, single-arm, phase II trial of patients with platinum-sensitive recurrent ovarian cancer recruited from seven KGOG sites. This study included patients with platinum-sensitive recurrent epithelial ovarian cancer who received at least 2 previous courses of platinum-containing therapy and had been treated with a PARPi. Mucinous histology type was excluded. Patients who had responded to the last platinum regimen (either complete or partial response) were eligible to participate in this study. Forty-four patients will be recruited. All enrolled patients are treated with niraparib and bevacizumab for maintenance therapy until disease progression, unacceptable toxicity, or withdrawal of patient consent. The primary endpoint of the study is 6-month progression-free survival rate. Accrual is expected to be completed in 2022, followed by presentation of results in 2023.

Trial registration

ClinicalTrials.gov Identifier: NCT04734665.

SUBMITTER: Park J

PROVIDER: S-EPMC8899880 | biostudies-literature | 2022 Mar

REPOSITORIES: biostudies-literature

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Publications

A single-arm, phase II study of niraparib and bevacizumab maintenance therapy in platinum-sensitive, recurrent ovarian cancer patients previously treated with a PARP inhibitor: Korean Gynecologic Oncology Group (KGOG 3056)/NIRVANA-R trial.

Park Junsik J Lim Myong Cheol MC Lee Jae-Kwan JK Jeong Dae Hoon DH Kim Se Ik SI Choi Min Chul MC Kim Byoung-Gie BG Lee Jung-Yun JY

Journal of gynecologic oncology 20211206 2

<h4>Background</h4>Given the expanding clinical use of poly(adenosine diphosphate [ADP]-ribose) polymerase inhibitors (PARPis), there is a significant need for optimal strategies with which to treat patients whose cancer progresses while using a PARPi. However, the treatment consensus after PARPi has not been established. The aim of the Korean Gynecologic Oncology Group (KGOG) 3056/NIRVANA-R trial is to investigate the efficacy of niraparib in combination with bevacizumab as a maintenance therap ...[more]

PMID: 34910393

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Project description:PurposeThe vascular disrupting agent fosbretabulin tromethamine selectively targets pre-existing tumor vasculature, which causes vascular shutdown and leads to cancer cell death and necrosis. Antiangiogenesis agents such as bevacizumab, a humanized antivascular endothelial growth factor monoclonal antibody, might prevent revascularization during and after treatment with a vascular disrupting agent.Patients and methodsPatients with recurrent or persistent epithelial ovarian, tubal, or peritoneal carcinoma, measurable or detectable disease, and three or fewer prior regimens were randomly assigned to bevacizumab (15 mg/kg intravenously once every 3 weeks) or the combination of bevacizumab (15 mg/kg) plus fosbretabulin (60 mg/m(2)) intravenously once every 3 weeks until disease progression or toxicity. Randomization was stratified by disease status (measurable v nonmeasurable), prior bevacizumab, and platinum-free interval. The primary end point was progression-free survival (PFS). The study was designed with 80% power for a one-sided alternative at a 10% level of significance to detect a reduction in the hazard by 37.5%.ResultsThe study enrolled 107 patients. Median PFS was 4.8 months for bevacizumab and 7.3 months for bevacizumab plus fosbretabulin (hazard ratio, 0.69; 90% two-sided CI, 0.47 to 1.00; one-sided P = .05). The proportion responding (overall response rate) to bevacizumab was 28.2% among 39 patients with measurable disease and 35.7% among 42 patients treated with the combination. The relative probability of responding was 1.27 (90% CI, 0.74 to 2.17; one-sided P = .24). Adverse events greater than grade 3 were more common in the combination regimen than in bevacizumab only for hypertension (35% v 20%). There was one grade 3 thromboembolic event in the combination arm and one intestinal fistula in the bevacizumab only arm.ConclusionOn the basis of the PFS, overall response rate, and tolerability of these two antivascular therapies, further evaluation is warranted for this chemotherapy-free regimen. Fosbretabulin in combination with bevacizumab increases the risk of hypertension.

Project description:ObjectiveManagement of heavily pre-treated platinum-resistant ovarian cancer remains a therapeutic challenge. Outcomes are poor with non-platinum, single-agent chemotherapy (CT); however, molecularly targeted anticancer therapies provide new options.MethodsThis open-label, investigator-initiated, phase 2 umbrella trial (NCT03699449) enrolled patients with platinum-resistant ovarian cancer (at least 2 prior lines of CT and Eastern Cooperative Oncology Group 0/1) to receive combination therapy based on homologous recombination deficiency (HRD) and programmed death ligand 1 (PD-L1) status determined by archival tumour sample assessment. HRD-positive patients were randomised to either olaparib 200mg bid tablet + cediranib 30mg qd (arm 1) or olaparib 300mg bid tablet + durvalumab 1,500mg q4w (arm 2). HRD-negative patients were allocated to either durvalumab 1,500 mg q4w + pegylated liposomal doxorubicin (PLD) or topotecan or weekly paclitaxel (6 cycles; arm 3, those with PD-L1 expression) or durvalumab 1,500 mg q4w + tremelimumab 75mg q4w (4 doses) + PLD or topotecan or weekly paclitaxel (4 cycles; arm 4, those without PD-L1 expression). Arm 5 (durvalumab 1,500 mg q4w + tremelimumab 300mg [1 dose] + weekly paclitaxel [60 mg/m² D1,8,15 q4w for 4 cycles] was initiated after arm 4 completed. The primary endpoint was objective response rate (ORR; Response Evaluation Criteria in Solid Tumours 1.1).ResultsBetween Dec 2018 and Oct 2020, 70 patients (median 57 years; median 3 prior treatment lines [range 2-10]) were treated (n=16, 14, 5, 18, and 17, respectively). Overall ORR was 37.1% (26/70, 95% confidence interval=25.9, 49.5); 2 achieved complete response. ORR was 50%, 42.9%, 20%, 33.3%, and 29.4%, respectively. Grade 3/4 treatment-related adverse events (TRAEs) were reported in 37.5%, 35.7%, 20%, 66.7%, and 35.3% of patients, respectively. No TRAEs leading to treatment discontinuation and no grade 5 TRAEs were observed.ConclusionThis study, the first biomarker-driven umbrella trial in platinum-resistant recurrent ovarian cancer, suggests clinical utility with biomarker-driven targeted therapy. All treatment combinations were manageable, and without unexpected toxicities.Trial registrationClinicalTrials.gov Identifier: NCT03699449.

Project description:Poly (ADP-ribose) polymerases (PARPs) are an important family of nucleoproteins highly implicated in DNA damage repair. Among the PARP families, the most studied are PARP1, PARP2 and PARP 3. PARP1 is found to be the most abundant nuclear enzyme under the PARP series. These enzymes are primarily involved in base excision repair as one of the major single strand break (SSB) repair mechanisms. Being double stranded, DNA engages itself in reparation of a sub-lethal SSB with the aid of PARP. Moreover, by having a sister chromatid, DNA can also repair double strand breaks with either error-free homologous recombination or error-prone non-homologous end-joining. For effective homologous recombination repair, DNA requires functional heterozygous breast cancer genes (BRCA) which encode BRCA1/2. Currently, the development of PARP inhibitors has been one of the promising breakthroughs for cancer chemotherapy. In March 2017, the United States Food and Drug Administration (FDA) approved niraparib for maintenance therapy of recurrent gynecologic cancers (epithelial ovarian, primary peritoneal and fallopian tube carcinomas) which are sensitive to previous platinum based chemotherapy irrespective of BRCA mutation and homologous recombination deficiency status. It is the third drug in this class to receive FDA approval, following olaparib and rucaparib and is the first global approval for maintenance therapy of the aforementioned cancers. Niraparib preferentially blocks both PARP1 and PARP2 enzymes. The daily tolerated dose of niraparib is 300 mg, above which dose limiting grade 3 and 4 toxicities were observed. In combination with humanized antibody, pembrolizumab, it is also under investigation for those patients who have triple negative breast cancer. By and large, there are several clinical trials that are underway investigating clinical efficacy and safety, as well as other pharmacokinetic and pharmacodynamic profiles of this drug for various malignancies.

Dataset Information

A single-arm, phase II study of niraparib and bevacizumab maintenance therapy in platinum-sensitive, recurrent ovarian cancer patients previously treated with a PARP inhibitor: Korean Gynecologic Oncology Group (KGOG 3056)/NIRVANA-R trial.

Background

Methods

Trial registration

Publications

A single-arm, phase II study of niraparib and bevacizumab maintenance therapy in platinum-sensitive, recurrent ovarian cancer patients previously treated with a PARP inhibitor: Korean Gynecologic Oncology Group (KGOG 3056)/NIRVANA-R trial.

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