Phase I/II Study of the WEE1 Inhibitor Adavosertib (AZD1775) in Combination with Carboplatin in Children with Advanced Malignancies : Arm C of the AcSé-ESMART Trial
©2023 American Association for Cancer Research..
PURPOSE: AcSé-ESMART Arm C aimed to define the recommended dose and activity of the WEE1 inhibitor adavosertib in combination with carboplatin in children and young adults with molecularly enriched recurrent/refractory malignancies.
PATIENTS AND METHODS: Adavosertib was administered orally, twice every day on Days 1 to 3 and carboplatin intravenously on Day 1 of a 21-day cycle, starting at 100 mg/m2/dose and AUC 5, respectively. Patients were enriched for molecular alterations in cell cycle and/or homologous recombination (HR).
RESULTS: Twenty patients (median age: 14.0 years; range: 3.4-23.5) were included; 18 received 69 treatment cycles. Dose-limiting toxicities were prolonged grade 4 neutropenia and grade 3/4 thrombocytopenia requiring transfusions, leading to two de-escalations to adavosertib 75 mg/m2/dose and carboplatin AUC 4; no recommended phase II dose was defined. Main treatment-related toxicities were hematologic and gastrointestinal. Adavosertib exposure in children was equivalent to that in adults; both doses achieved the cell kill target. Overall response rate was 11% (95% confidence interval, 0.0-25.6) with partial responses in 2 patients with neuroblastoma. One patient with medulloblastoma experienced unconfirmed partial response and 5 patients had stable disease beyond four cycles. Seven of these eight patients with clinical benefit had alterations in HR, replication stress, and/or RAS pathway genes with or without TP53 alterations, whereas TP53 pathway alterations alone (8/10) or no relevant alterations (2/10) were present in the 10 patients without benefit.
CONCLUSIONS: Adavosertib-carboplatin combination exhibited significant hematologic toxicity. Activity signals and identified potential biomarkers suggest further studies with less hematotoxic DNA-damaging therapy in molecularly enriched pediatric cancers.
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2024 |
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| Erschienen: |
2024 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:30 |
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| Enthalten in: |
Clinical cancer research : an official journal of the American Association for Cancer Research - 30(2024), 4 vom: 16. Feb., Seite 741-753 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Gatz, Susanne A [VerfasserIn] |
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| Links: |
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| Anmerkungen: |
Date Completed 19.02.2024 Date Revised 20.03.2024 published: Print Citation Status MEDLINE |
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| doi: |
10.1158/1078-0432.CCR-23-2959 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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| 100 | 1 | |a Gatz, Susanne A |e verfasserin |4 aut | |
| 245 | 1 | 0 | |a Phase I/II Study of the WEE1 Inhibitor Adavosertib (AZD1775) in Combination with Carboplatin in Children with Advanced Malignancies |b Arm C of the AcSé-ESMART Trial |
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| 500 | |a Date Completed 19.02.2024 | ||
| 500 | |a Date Revised 20.03.2024 | ||
| 500 | |a published: Print | ||
| 500 | |a Citation Status MEDLINE | ||
| 520 | |a ©2023 American Association for Cancer Research. | ||
| 520 | |a PURPOSE: AcSé-ESMART Arm C aimed to define the recommended dose and activity of the WEE1 inhibitor adavosertib in combination with carboplatin in children and young adults with molecularly enriched recurrent/refractory malignancies | ||
| 520 | |a PATIENTS AND METHODS: Adavosertib was administered orally, twice every day on Days 1 to 3 and carboplatin intravenously on Day 1 of a 21-day cycle, starting at 100 mg/m2/dose and AUC 5, respectively. Patients were enriched for molecular alterations in cell cycle and/or homologous recombination (HR) | ||
| 520 | |a RESULTS: Twenty patients (median age: 14.0 years; range: 3.4-23.5) were included; 18 received 69 treatment cycles. Dose-limiting toxicities were prolonged grade 4 neutropenia and grade 3/4 thrombocytopenia requiring transfusions, leading to two de-escalations to adavosertib 75 mg/m2/dose and carboplatin AUC 4; no recommended phase II dose was defined. Main treatment-related toxicities were hematologic and gastrointestinal. Adavosertib exposure in children was equivalent to that in adults; both doses achieved the cell kill target. Overall response rate was 11% (95% confidence interval, 0.0-25.6) with partial responses in 2 patients with neuroblastoma. One patient with medulloblastoma experienced unconfirmed partial response and 5 patients had stable disease beyond four cycles. Seven of these eight patients with clinical benefit had alterations in HR, replication stress, and/or RAS pathway genes with or without TP53 alterations, whereas TP53 pathway alterations alone (8/10) or no relevant alterations (2/10) were present in the 10 patients without benefit | ||
| 520 | |a CONCLUSIONS: Adavosertib-carboplatin combination exhibited significant hematologic toxicity. Activity signals and identified potential biomarkers suggest further studies with less hematotoxic DNA-damaging therapy in molecularly enriched pediatric cancers | ||
| 650 | 4 | |a Clinical Trial, Phase II | |
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