Phase I study of continuous olaparib capsule dosing in combination with carboplatin and/or paclitaxel (Part 1)
Background The PARP inhibitor olaparib has shown acceptable toxicity at doses of up to 400 mg twice daily (bid; capsule formulation) with encouraging signs of antitumor activity. Based on its mode of action, olaparib may sensitize tumor cells to DNA-damaging agents. This Phase I trial (NCT00516724) evaluated the safety, pharmacokinetics (PK) and preliminary efficacy of olaparib combined with carboplatin and/or paclitaxel. Methods Patients with advanced solid tumors received olaparib (capsule bid) plus carboplatin (Part A), carboplatin and paclitaxel (Part B), or paclitaxel (Part C). In each part of the study, different drug doses were given to define the most appropriate dose/drug combination to use in further studies. Safety assessments included evaluation of dose-limiting toxicities (DLTs; cycle 1 only), adverse events (AEs) and physical examinations. PK assessments of olaparib, carboplatin and paclitaxel were performed. Tumor responses (RECIST) were assessed every two cycles. Results Fifty-seven patients received treatment. DLTs were reported in two patients (both receiving olaparib 100 mg bid and carboplatin AUC 4; Part A, cohort 2): grade 1 thrombocytopenia with grade 2 neutropenia lasting for 16 days, and grade 2 neutropenia lasting for 7 days. Non-hematologic AEs were predominantly grade 1-2 and included fatigue (70%) and nausea (40%). Bone marrow suppression, mainly neutropenia (51%) and thrombocytopenia (25%), frequently led to dose modifications. Conclusions Olaparib in combination with carboplatin and/or paclitaxel resulted in increased hematologic toxicities, making it challenging to establish a dosing regimen that could be tolerated for multiple cycles without dose modifications.
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2020 |
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| Erschienen: |
2020 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:38 |
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| Enthalten in: |
Investigational new drugs - 38(2020), 4 vom: 30. Aug., Seite 1117-1128 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
van der Noll, Ruud [VerfasserIn] |
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| Links: |
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| Anmerkungen: |
Date Completed 09.09.2021 Date Revised 09.09.2021 published: Print-Electronic ClinicalTrials.gov: NCT00516724 Citation Status MEDLINE |
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| doi: |
10.1007/s10637-019-00856-7 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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| PPN (Katalog-ID): |
NLM302721533 |
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| 500 | |a Date Completed 09.09.2021 | ||
| 500 | |a Date Revised 09.09.2021 | ||
| 500 | |a published: Print-Electronic | ||
| 500 | |a ClinicalTrials.gov: NCT00516724 | ||
| 500 | |a Citation Status MEDLINE | ||
| 520 | |a Background The PARP inhibitor olaparib has shown acceptable toxicity at doses of up to 400 mg twice daily (bid; capsule formulation) with encouraging signs of antitumor activity. Based on its mode of action, olaparib may sensitize tumor cells to DNA-damaging agents. This Phase I trial (NCT00516724) evaluated the safety, pharmacokinetics (PK) and preliminary efficacy of olaparib combined with carboplatin and/or paclitaxel. Methods Patients with advanced solid tumors received olaparib (capsule bid) plus carboplatin (Part A), carboplatin and paclitaxel (Part B), or paclitaxel (Part C). In each part of the study, different drug doses were given to define the most appropriate dose/drug combination to use in further studies. Safety assessments included evaluation of dose-limiting toxicities (DLTs; cycle 1 only), adverse events (AEs) and physical examinations. PK assessments of olaparib, carboplatin and paclitaxel were performed. Tumor responses (RECIST) were assessed every two cycles. Results Fifty-seven patients received treatment. DLTs were reported in two patients (both receiving olaparib 100 mg bid and carboplatin AUC 4; Part A, cohort 2): grade 1 thrombocytopenia with grade 2 neutropenia lasting for 16 days, and grade 2 neutropenia lasting for 7 days. Non-hematologic AEs were predominantly grade 1-2 and included fatigue (70%) and nausea (40%). Bone marrow suppression, mainly neutropenia (51%) and thrombocytopenia (25%), frequently led to dose modifications. Conclusions Olaparib in combination with carboplatin and/or paclitaxel resulted in increased hematologic toxicities, making it challenging to establish a dosing regimen that could be tolerated for multiple cycles without dose modifications | ||
| 650 | 4 | |a Clinical Trial, Phase I | |
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a Research Support, Non-U.S. Gov't | |
| 650 | 4 | |a Carboplatin | |
| 650 | 4 | |a Olaparib | |
| 650 | 4 | |a PARP inhibitor | |
| 650 | 4 | |a Paclitaxel | |
| 650 | 4 | |a Pharmacokinetics | |
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| 700 | 1 | |a Mergui-Roelvink, Marja W J |e verfasserin |4 aut | |
| 700 | 1 | |a Lolkema, Martijn P |e verfasserin |4 aut | |
| 700 | 1 | |a de Jonge, Maja J A |e verfasserin |4 aut | |
| 700 | 1 | |a van der Biessen, Diane A |e verfasserin |4 aut | |
| 700 | 1 | |a Brunetto, Andre T |e verfasserin |4 aut | |
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| 700 | 1 | |a Tchakov, Ilian |e verfasserin |4 aut | |
| 700 | 1 | |a Beijnen, Jos H |e verfasserin |4 aut | |
| 700 | 1 | |a de Bono, Johann S |e verfasserin |4 aut | |
| 700 | 1 | |a Schellens, Jan H M |e verfasserin |4 aut | |
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