In:
Journal of Clinical Oncology, American Society of Clinical Oncology (ASCO), Vol. 40, No. 16_suppl ( 2022-06-01), p. TPS11584-TPS11584
Kurzfassung:
TPS11584 Background: Osteosarcoma (OS) is the most common primary bone malignancy of childhood and adolescence with 5-year survival rates of 65-70% for localized disease and 〈 30% for de novo metastatic disease or recurrent disease. Pooled analysis of previous phase 2 trials by the Children’s Oncology Group has determined a 4-month event-free survival (EFS) of 12%. The Wee1 kinase helps regulate DNA damage repair at the G2-M checkpoint. In the presence of DNA damage, the Wee1 kinase is activated, arresting cells in the G2 phase and preventing entry into the M phase. Inhibition of the Wee1 kinase abrogates the G2-M checkpoint, forcing cancer cells to undergo unscheduled mitosis even in the presence of DNA damage, leading to mitotic catastrophe. However, the Wee1 kinase is often upregulated in OS, preserving the G2-M checkpoint and allowing tumor growth and metastases. Additionally, up to 90% of OS tumors have alterations in p53, a critical protein in the regulation of the G1-S checkpoint, especially in relapsed or refractory cases. With a dysfunctional G1-S checkpoint, cancer cells further rely on G2-M checkpoint to repair DNA damage and preserve genomic integrity. Prior studies have demonstrated that pharmacologic inhibition of the Wee1 kinase produced cell death in OS cell lines and patient-derived xenografts. While p53 mutational status appeared to modulate efficacy of the Wee1 kinase inhibitor, activity was observed in p53 wild type, mutant and null cell lines. Combination therapy studies have also been performed, demonstrating potential synergism with gemcitabine. As expected, by precipitating DNA damage, susceptibility to inhibition of the G2-M checkpoint is further increased. Methods: NCT04833582 is an ongoing, open label, multicenter, phase 1/2 clinical trial to evaluate the activity of ZN-c3, an oral Wee1 inhibitor, in combination with gemcitabine in subjects ≥12 years and ≥40 kg, with relapsed, refractory OS. Subjects are dosed once daily, continuously with ZN-c3 and receive gemcitabine 1000 mg/m 2 on days 1 and 8 of 21-day cycles. Up to 18 subjects are expected to enroll in the phase 1 portion based on a typical 3 + 3 escalation design; ̃60 subjects will be enrolled in the phase 2 portion, consisting of three stages: futility, promising clinical activity, and improved precision for clinical activity. The first two stages follow a Simon two-stage optimal design with 30 subjects, to differentiate an EFS rate at 18 weeks between 12% and 36% (which may be considered a more suitable endpoint for OS, compared with radiographic response). Tumor and skin punch biopsies are incorporated into the trial to identify potential biomarkers of treatment response. Subjects must be able to swallow oral tablets and have measurable disease by RECIST v1.1; prior exposure to gemcitabine is allowed. Global enrollment began August 1, 2021, and is ongoing. Clinical trial information: NCT04833582.
Materialart:
Online-Ressource
ISSN:
0732-183X
,
1527-7755
DOI:
10.1200/JCO.2022.40.16_suppl.TPS11584
Sprache:
Englisch
Verlag:
American Society of Clinical Oncology (ASCO)
Publikationsdatum:
2022
ZDB Id:
2005181-5
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