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 - Centre Oscar Lambret Accéder directement au contenu
Article Dans Une Revue Clinical Cancer Research Année : 2023

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

Samuel Abbou
Kowser Miah
Peter G.S. Mortimer
Gilles Vassal

Résumé

Abstract 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.
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inserm-04590103 , version 1 (28-05-2024)

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Susanne A Gatz, Anne C Harttrampf, Caroline Brard, Francisco Bautista, Nicolas André, et al.. 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. Clinical Cancer Research, 2023, 30 (4), pp.741 - 753. ⟨10.1158/1078-0432.ccr-23-2959⟩. ⟨inserm-04590103⟩
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