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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

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...

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Hauptverfasser: Gatz, Susanne Andrea (VerfasserIn) , Harttrampf, Anne C. (VerfasserIn) , Brard, Caroline (VerfasserIn) , Bautista, Francisco (VerfasserIn) , André, Nicolas (VerfasserIn) , Abbou, Samuel (VerfasserIn) , Rubino, Jonathan (VerfasserIn) , Rondof, Windy (VerfasserIn) , Deloger, Marc (VerfasserIn) , Rübsam, Marc (VerfasserIn) , Marshall, Lynley V. (VerfasserIn) , Hübschmann, Daniel (VerfasserIn) , Nebchi, Souad (VerfasserIn) , Aerts, Isabelle (VerfasserIn) , Thebaud, Estelle (VerfasserIn) , De Carli, Emilie (VerfasserIn) , Defachelles, Anne Sophie (VerfasserIn) , Paoletti, Xavier (VerfasserIn) , Godin, Robert (VerfasserIn) , Miah, Kowser (VerfasserIn) , Mortimer, Peter G. S. (VerfasserIn) , Vassal, Gilles (VerfasserIn) , Geoerger, Birgit (VerfasserIn)
Dokumenttyp: Article (Journal)
Sprache:Englisch
Veröffentlicht: 2024
In: Clinical cancer research
Year: 2024, Jahrgang: 30, Heft: 4, Pages: 741-753
ISSN:1557-3265
DOI:10.1158/1078-0432.CCR-23-2959
Online-Zugang:Verlag, lizenzpflichtig, Volltext: https://doi.org/10.1158/1078-0432.CCR-23-2959
Volltext
Verfasserangaben:Susanne A. Gatz, Anne C. Harttrampf, Caroline Brard, Francisco Bautista, Nicolas André, Samuel Abbou, Jonathan Rubino, Windy Rondof, Marc Deloger, Marc Rübsam, Lynley V. Marshall, Daniel Hübschmann, Souad Nebchi, Isabelle Aerts, Estelle Thebaud, Emilie De Carli, Anne Sophie Defachelles, Xavier Paoletti, Robert Godin, Kowser Miah, Peter G.S. Mortimer, Gilles Vassal, and Birgit Geoerger
Beschreibung
Zusammenfassung: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.
Beschreibung:Online verfügbar: December 5, 2023
Gesehen am 25.10.2024
Beschreibung:Online Resource
ISSN:1557-3265
DOI:10.1158/1078-0432.CCR-23-2959

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