A phase 1 trial of fuzuloparib in combination with apatinib for advanced ovarian and triple-negative breast cancer: efficacy, safety, pharmacokinetics and germline BRCA mutation analysis
Abstract Background The effect of the combination of an anti-angiogenic agent with a poly (ADP-ribose) polymerase (PARP) inhibitor in cancer treatment is unclear. We assessed the oral combination of fuzuloparib, a PARP inhibitor, and apatinib, a VEGFR2 inhibitor for treating advanced ovarian cancer...
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| Language: | English |
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BMC
2023-09-01
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| Series: | BMC Medicine |
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| Online Access: | https://doi.org/10.1186/s12916-023-03046-8 |
| _version_ | 1797452354460581888 |
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| author | Yaxin Liu Wei Wang Rutie Yin Youzhong Zhang Yu Zhang Keqiang Zhang Hongming Pan Ke Wang Ge Lou Guiling Li Ruyan Zhang Kun Li Jing Rao Ben Zhang Yuting Wang Quanren Wang Yunong Gao Huiping Li |
| author_facet | Yaxin Liu Wei Wang Rutie Yin Youzhong Zhang Yu Zhang Keqiang Zhang Hongming Pan Ke Wang Ge Lou Guiling Li Ruyan Zhang Kun Li Jing Rao Ben Zhang Yuting Wang Quanren Wang Yunong Gao Huiping Li |
| author_sort | Yaxin Liu |
| collection | DOAJ |
| description | Abstract Background The effect of the combination of an anti-angiogenic agent with a poly (ADP-ribose) polymerase (PARP) inhibitor in cancer treatment is unclear. We assessed the oral combination of fuzuloparib, a PARP inhibitor, and apatinib, a VEGFR2 inhibitor for treating advanced ovarian cancer (OC) or triple-negative breast cancer (TNBC). Methods This dose-escalation and pharmacokinetics-expansion phase 1 trial was conducted in China. We used a standard 3 + 3 dose-escalation design, with 7 dose levels tested. Patients received fuzuloparib orally twice daily, and apatinib orally once daily. The study objectives were to determine the safety profile, recommended phase 2 dose (RP2D), pharmacokinetics, preliminary efficacy, and efficacy in relation to germline BRCA mutation (gBRCA mut). Results Fifty-two pre-treated patients were enrolled (30 OC/22 TNBC). 5 (9.6%) patients had complete response, 14 (26.9%) had partial response, and 15 (28.8%) had stable disease. Objective response rate (ORR) and disease control rate were 36.5% (95% CI 23.6–51.0) and 65.4% (95% CI 50.9–78.0), respectively. At the highest dose level of fuzuloparib 100 mg plus apatinib 500 mg, the ORR was 50.0% (4/8; 95% CI 15.7–84.3); this dose was determined to be the RP2D. Patients with gBRCA mut had higher ORR and longer median progression-free survival (PFS) than those with gBRCA wt, both in OC (ORR, 62.5% [5/8] vs 40.9% [9/22]; PFS, 9.4 vs 6.7 months) and TNBC (ORR, 66.7% [2/3] vs 15.8% [3/19]; PFS, 5.6 vs 2.8 months). Two dose-limiting toxicities occurred: grade 4 febrile neutropenia (fuzuloparib 100 mg plus apatinib 250 mg) and thrombocytopenia (fuzuloparib 100 mg plus apatinib 375 mg). Maximum tolerated dose was not reached. The most common treatment-related grade ≥ 3 toxicities in all patients were hypertension (19.2%), anaemia (13.5%), and decreased platelet count (5.8%). Exposure of apatinib increased proportionally with increasing dose ranging from 250 to 500 mg, when combined with fuzuloparib 100 mg. Conclusions Fuzuloparib plus apatinib had acceptable safety in patients with advanced OC or TNBC. Fuzuloparib 100 mg bid plus apatinib 500 mg qd was established as the RP2D. With the promising clinical activity observed, this combination is warranted to be further explored as a potential alternative to chemotherapy. Trial registration ClinicalTrials.gov, NCT03075462 (Mar. 9, 2017). |
| first_indexed | 2024-03-09T15:07:37Z |
| format | Article |
| id | doaj.art-25e642e1f9ec4ff7949cab5b7d9f0206 |
| institution | Directory Open Access Journal |
| issn | 1741-7015 |
| language | English |
| last_indexed | 2024-03-09T15:07:37Z |
| publishDate | 2023-09-01 |
| publisher | BMC |
| record_format | Article |
| series | BMC Medicine |
| spelling | doaj.art-25e642e1f9ec4ff7949cab5b7d9f02062023-11-26T13:34:03ZengBMCBMC Medicine1741-70152023-09-0121111010.1186/s12916-023-03046-8A phase 1 trial of fuzuloparib in combination with apatinib for advanced ovarian and triple-negative breast cancer: efficacy, safety, pharmacokinetics and germline BRCA mutation analysisYaxin Liu0Wei Wang1Rutie Yin2Youzhong Zhang3Yu Zhang4Keqiang Zhang5Hongming Pan6Ke Wang7Ge Lou8Guiling Li9Ruyan Zhang10Kun Li11Jing Rao12Ben Zhang13Yuting Wang14Quanren Wang15Yunong Gao16Huiping Li17Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Department of Breast Oncology, Peking University Cancer Hospital and InstituteKey Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Department of Gynecologic Cancer Surgery Unit, Peking University Cancer Hospital and InstituteRadiation Therapy and Chemotherapy for Gynecologic Cancer, West China Second University Hospital, Sichuan UniversityDepartment of Obstetrics and Gynecology, Qilu Hospital of Shangdong UniversityMedical Ethics Committee, Xiangya Hospital, Central South UniversityGynecologic Oncology Ward V, Hunan Cancer HospitalDepartment of Medical Oncology, Sir Run Run Shaw Hospital, Zhejiang University School of MedicineDepartment of Gynecologic Oncology, Tianjin Medical University Cancer Institute and HospitalGynecology Ward 1, Harbin Medical University Cancer HospitalDepartment of Gynecologic Oncology, Union Hospital, Tongji Medical College, Huazhong University of Science and TechnologyKey Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Department of Breast Oncology, Peking University Cancer Hospital and InstituteKey Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Department of Breast Oncology, Peking University Cancer Hospital and InstituteJiangsu Hengrui Pharmaceuticals Co., LtdJiangsu Hengrui Pharmaceuticals Co., LtdJiangsu Hengrui Pharmaceuticals Co., LtdJiangsu Hengrui Pharmaceuticals Co., LtdKey Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Department of Gynecologic Cancer Surgery Unit, Peking University Cancer Hospital and InstituteKey Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Department of Breast Oncology, Peking University Cancer Hospital and InstituteAbstract Background The effect of the combination of an anti-angiogenic agent with a poly (ADP-ribose) polymerase (PARP) inhibitor in cancer treatment is unclear. We assessed the oral combination of fuzuloparib, a PARP inhibitor, and apatinib, a VEGFR2 inhibitor for treating advanced ovarian cancer (OC) or triple-negative breast cancer (TNBC). Methods This dose-escalation and pharmacokinetics-expansion phase 1 trial was conducted in China. We used a standard 3 + 3 dose-escalation design, with 7 dose levels tested. Patients received fuzuloparib orally twice daily, and apatinib orally once daily. The study objectives were to determine the safety profile, recommended phase 2 dose (RP2D), pharmacokinetics, preliminary efficacy, and efficacy in relation to germline BRCA mutation (gBRCA mut). Results Fifty-two pre-treated patients were enrolled (30 OC/22 TNBC). 5 (9.6%) patients had complete response, 14 (26.9%) had partial response, and 15 (28.8%) had stable disease. Objective response rate (ORR) and disease control rate were 36.5% (95% CI 23.6–51.0) and 65.4% (95% CI 50.9–78.0), respectively. At the highest dose level of fuzuloparib 100 mg plus apatinib 500 mg, the ORR was 50.0% (4/8; 95% CI 15.7–84.3); this dose was determined to be the RP2D. Patients with gBRCA mut had higher ORR and longer median progression-free survival (PFS) than those with gBRCA wt, both in OC (ORR, 62.5% [5/8] vs 40.9% [9/22]; PFS, 9.4 vs 6.7 months) and TNBC (ORR, 66.7% [2/3] vs 15.8% [3/19]; PFS, 5.6 vs 2.8 months). Two dose-limiting toxicities occurred: grade 4 febrile neutropenia (fuzuloparib 100 mg plus apatinib 250 mg) and thrombocytopenia (fuzuloparib 100 mg plus apatinib 375 mg). Maximum tolerated dose was not reached. The most common treatment-related grade ≥ 3 toxicities in all patients were hypertension (19.2%), anaemia (13.5%), and decreased platelet count (5.8%). Exposure of apatinib increased proportionally with increasing dose ranging from 250 to 500 mg, when combined with fuzuloparib 100 mg. Conclusions Fuzuloparib plus apatinib had acceptable safety in patients with advanced OC or TNBC. Fuzuloparib 100 mg bid plus apatinib 500 mg qd was established as the RP2D. With the promising clinical activity observed, this combination is warranted to be further explored as a potential alternative to chemotherapy. Trial registration ClinicalTrials.gov, NCT03075462 (Mar. 9, 2017).https://doi.org/10.1186/s12916-023-03046-8Ovarian cancerTriple-negative breast cancerPARP inhibitorAnti-angiogenic therapygBRCA |
| spellingShingle | Yaxin Liu Wei Wang Rutie Yin Youzhong Zhang Yu Zhang Keqiang Zhang Hongming Pan Ke Wang Ge Lou Guiling Li Ruyan Zhang Kun Li Jing Rao Ben Zhang Yuting Wang Quanren Wang Yunong Gao Huiping Li A phase 1 trial of fuzuloparib in combination with apatinib for advanced ovarian and triple-negative breast cancer: efficacy, safety, pharmacokinetics and germline BRCA mutation analysis BMC Medicine Ovarian cancer Triple-negative breast cancer PARP inhibitor Anti-angiogenic therapy gBRCA |
| title | A phase 1 trial of fuzuloparib in combination with apatinib for advanced ovarian and triple-negative breast cancer: efficacy, safety, pharmacokinetics and germline BRCA mutation analysis |
| title_full | A phase 1 trial of fuzuloparib in combination with apatinib for advanced ovarian and triple-negative breast cancer: efficacy, safety, pharmacokinetics and germline BRCA mutation analysis |
| title_fullStr | A phase 1 trial of fuzuloparib in combination with apatinib for advanced ovarian and triple-negative breast cancer: efficacy, safety, pharmacokinetics and germline BRCA mutation analysis |
| title_full_unstemmed | A phase 1 trial of fuzuloparib in combination with apatinib for advanced ovarian and triple-negative breast cancer: efficacy, safety, pharmacokinetics and germline BRCA mutation analysis |
| title_short | A phase 1 trial of fuzuloparib in combination with apatinib for advanced ovarian and triple-negative breast cancer: efficacy, safety, pharmacokinetics and germline BRCA mutation analysis |
| title_sort | phase 1 trial of fuzuloparib in combination with apatinib for advanced ovarian and triple negative breast cancer efficacy safety pharmacokinetics and germline brca mutation analysis |
| topic | Ovarian cancer Triple-negative breast cancer PARP inhibitor Anti-angiogenic therapy gBRCA |
| url | https://doi.org/10.1186/s12916-023-03046-8 |
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