A phase 1 dose-escalation study of the poly(ADP-ribose) polymerase inhibitor senaparib in Australian patients with advanced solid tumors
© 2023 The Authors. Cancer published by Wiley Periodicals LLC on behalf of American Cancer Society..
BACKGROUND: Senaparib is a novel, selective poly(ADP-ribose) polymerase-1/2 inhibitor with strong antitumor activity in preclinical studies. This first-in-human, phase 1, dose-escalation study examined the safety and preliminary efficacy of senaparib in patients with advanced solid tumors.
METHODS: Patients with advanced solid tumors were enrolled from three centers in Australia, using a conventional 3 + 3 design. Dose-escalation cohorts continued until the maximum tolerated dose or a recommended phase 2 dose was determined. Patients received one dose of oral senaparib and, if no dose-limiting toxicity occurred within 7 days, they received senaparib once daily in 3-week cycles. The primary end points were safety and tolerability.
RESULTS: Thirty-nine patients were enrolled at 10 dose levels ranging from 2 to 150 mg. No dose-limiting toxicities were observed in any cohort. Most treatment-emergent adverse events were grade 1-2 (91%). Seven patients (17.9%) reported hematologic treatment-emergent adverse events. Treatment-related adverse events occurred in eight patients (20.5%), and the most frequent was nausea (7.7%). Two deaths were reported after the end of study treatment, one of which was considered a complication from senaparib-related bone marrow failure. Pharmacokinetic analysis indicated that senaparib the accumulation index was 1.06-1.67, and absorption saturation was 80-150 mg daily. In 22 patients with evaluable disease, the overall response rate was 13.6%, and the disease control rate was 81.8%. The overall response rate was 33.3% for the BRCA mutation-positive subgroup and 6.3% for the nonmutated subgroup.
CONCLUSIONS: Senaparib was well tolerated in Australian patients with advanced solid tumors, with encouraging signals of antitumor activity. The recommended phase 2 dose for senaparib was determined to be 100 mg daily.
CLINICALTRIALS:.
GOV ID: NCT03507543.
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2023 |
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| Erschienen: |
2023 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:129 |
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| Enthalten in: |
Cancer - 129(2023), 7 vom: 01. Apr., Seite 1041-1050 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Gao, Bo [VerfasserIn] |
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| Links: |
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| Anmerkungen: |
Date Completed 10.03.2023 Date Revised 27.03.2023 published: Print-Electronic ClinicalTrials.gov: NCT03507543 Citation Status MEDLINE |
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| doi: |
10.1002/cncr.34662 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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| 245 | 1 | 2 | |a A phase 1 dose-escalation study of the poly(ADP-ribose) polymerase inhibitor senaparib in Australian patients with advanced solid tumors |
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| 500 | |a Date Revised 27.03.2023 | ||
| 500 | |a published: Print-Electronic | ||
| 500 | |a ClinicalTrials.gov: NCT03507543 | ||
| 500 | |a Citation Status MEDLINE | ||
| 520 | |a © 2023 The Authors. Cancer published by Wiley Periodicals LLC on behalf of American Cancer Society. | ||
| 520 | |a BACKGROUND: Senaparib is a novel, selective poly(ADP-ribose) polymerase-1/2 inhibitor with strong antitumor activity in preclinical studies. This first-in-human, phase 1, dose-escalation study examined the safety and preliminary efficacy of senaparib in patients with advanced solid tumors | ||
| 520 | |a METHODS: Patients with advanced solid tumors were enrolled from three centers in Australia, using a conventional 3 + 3 design. Dose-escalation cohorts continued until the maximum tolerated dose or a recommended phase 2 dose was determined. Patients received one dose of oral senaparib and, if no dose-limiting toxicity occurred within 7 days, they received senaparib once daily in 3-week cycles. The primary end points were safety and tolerability | ||
| 520 | |a RESULTS: Thirty-nine patients were enrolled at 10 dose levels ranging from 2 to 150 mg. No dose-limiting toxicities were observed in any cohort. Most treatment-emergent adverse events were grade 1-2 (91%). Seven patients (17.9%) reported hematologic treatment-emergent adverse events. Treatment-related adverse events occurred in eight patients (20.5%), and the most frequent was nausea (7.7%). Two deaths were reported after the end of study treatment, one of which was considered a complication from senaparib-related bone marrow failure. Pharmacokinetic analysis indicated that senaparib the accumulation index was 1.06-1.67, and absorption saturation was 80-150 mg daily. In 22 patients with evaluable disease, the overall response rate was 13.6%, and the disease control rate was 81.8%. The overall response rate was 33.3% for the BRCA mutation-positive subgroup and 6.3% for the nonmutated subgroup | ||
| 520 | |a CONCLUSIONS: Senaparib was well tolerated in Australian patients with advanced solid tumors, with encouraging signals of antitumor activity. The recommended phase 2 dose for senaparib was determined to be 100 mg daily | ||
| 520 | |a CLINICALTRIALS: | ||
| 520 | |a GOV ID: NCT03507543 | ||
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| 650 | 4 | |a senaparib | |
| 650 | 4 | |a solid tumors | |
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| 650 | 7 | |a Poly(ADP-ribose) Polymerase Inhibitors |2 NLM | |
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| 700 | 1 | |a Wilkinson, Kate |e verfasserin |4 aut | |
| 700 | 1 | |a Hoon, Siao |e verfasserin |4 aut | |
| 700 | 1 | |a Hsieh, Chih-Yi |e verfasserin |4 aut | |
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| 700 | 1 | |a Tian, Ye Edward |e verfasserin |4 aut | |
| 700 | 1 | |a Bao, Jun |e verfasserin |4 aut | |
| 700 | 1 | |a Ma, Ning |e verfasserin |4 aut | |
| 700 | 1 | |a Wang, Chen |e verfasserin |4 aut | |
| 700 | 1 | |a Zhang, Ming |e verfasserin |4 aut | |
| 700 | 1 | |a Li, Baoyue |e verfasserin |4 aut | |
| 700 | 1 | |a Guo, Mingchuan |e verfasserin |4 aut | |
| 700 | 1 | |a Zhou, Ruiyu |e verfasserin |4 aut | |
| 700 | 1 | |a Wang, Xiaozhu |e verfasserin |4 aut | |
| 700 | 1 | |a Xu, Cong |e verfasserin |4 aut | |
| 700 | 1 | |a de Souza, Paul |e verfasserin |4 aut | |
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