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- W4286294463 abstract "e15052 Background: WEE1 kinase is a cell-cycle regulator that is important in DNA repair, and a validated antitumor target. IMP7068 is a potent and selective WEE1 inhibitor that has demonstrated antitumor activity in preclinical pharmacological models. A first-in-human, multicenter, open-label study was conducted to evaluate the safety, tolerability, pharmacokinetic (PK) characteristics, pharmacodynamic (PD) profiles and preliminary antitumor activity of IMP7068 in patients (pts) with advanced solid tumors. Methods: This phase 1 study included both a dose-escalation and dose-expansion stage. The dose-escalation stage was designed with 6 dose cohorts of IMP7068 at 30, 60, 120, 200, 300, and 400 mg (administered orally, once daily [QD] for 3 days, followed by 4 days off weekly for 21-day cycles). An accelerated titration design was used for the 30- and 60-mg dose levels, and an i3+3 design for all doses > 60 mg. Pts were adults (age ≥18 years) with confirmed advanced solid tumors that were refractory or intolerant to standard treatment, or for which no standard treatment exists. The objectives of the dose-escalation stage were to evaluate the safety and tolerability, PK and PD profiles, and antitumor activity (per RECIST v1.1) of IMP7068. Results: As of Jan 7, 2022, 9 pts were enrolled in the dose-escalation phase (average age, 56 years). An additional cohort of IMP7068 160 mg was recommended by the Safety Monitoring Committee based on PK data from the 120-mg cohort. Pts received escalating doses at 30 mg (n = 1), 60 mg (n = 1), 120 mg (n = 3), and 160 mg (n = 4). No dose-limiting toxicities (DLTs) were observed. Treatment-related adverse events (TRAEs) occurred in 4 pts, most frequently alanine aminotransferase (ALT) increased, aspartate aminotransferase (AST) increased, and diarrhea (all in 2 pts each). Most TRAEs were grade 1 or 2 in severity; and only 1 patient had grade 3 TRAEs (AST and ALT increased). Time to reach the maximum plasma concentration of IMP7068 was approximately 2–6 hours following administration of 30–160 mg doses, respectively. Following repeated QD administration for 3 days, the accumulation ratios for IMP7068 exposure parameters C max and AUC 0-tau were 1.74–2.49 and 3.17–3.46, respectively, across the dose levels. The elimination half-life was approximately 10–28 hours after administration of 60–160 mg IMP7068. PD data showed that levels of phosphorylated cyclin-dependent kinase 1 decreased by ≥50% after treatment in the 160-mg cohort. Five of 8 evaluable pts had a best tumor response of stable disease (SD); 1 patient with colorectal cancer maintained a best response of SD for 22 weeks. Four pts remain on study. Conclusions: IMP7068 was well-tolerated with no DLTs, and conferred a meaningful PD effect and preliminary antitumor activity at doses of up to 160 mg in pts with advanced solid tumors. Dose escalation to establish the recommended phase 2 dose and/or maximum tolerated dose is continuing. Clinical trial information: NCT04768868." @default.
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- W4286294463 date "2022-06-01" @default.
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- W4286294463 title "A phase 1 dose-escalation and -expansion study of IMP7068, a WEE1 inhibitor, in patients with advanced solid tumors." @default.
- W4286294463 doi "https://doi.org/10.1200/jco.2022.40.16_suppl.e15052" @default.
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