Abstract
IntroductionAdvanced/recurrent endometrial cancer (EC) has poor prognosis with 5-year survival rate of ~17% (Colombo 2016; Siegel 2022). Maintenance treatment may extend the response to initial chemo/chemoimmunotherapy. Mouse double minute 2 (MDM2), a key negative regulator of p53, is upregulated in ~50% of EC patients (Jeczen 2007) due to loss of p14ARF, a critical modulator of intranuclear MDM2 levels, thus preventing p53 tumor suppressor function. Navtemadlin is a potent, selective MDM2 inhibitor that restores p53-mediated apoptosis in TP53WTtumors. The sensitivity of EC to genotoxic chemotherapy (Miller 2020) suggests susceptibility to p53-mediated apoptosis. Post-chemotherapy maintenance with navtemadlin may provide a non-genotoxic way to maintain p53-driven activity and tumor cell control in the ~50% of TP53WTEC patients (Nakamura 2019). KRT-232–118 is a Global 2-part Phase 2/3 study evaluating the safety and efficacy of navtemadlin maintenance therapy in TP53WT advanced/recurrent EC patients following response to chemotherapy (EudraCT 2022–5002196-31; NCT05797831).MethodsAdults with ECOG PS 0–1 who completed up to 6 cycles of chemotherapy excluding adjuvant/neo-adjuvant therapy and achieved CR or PR (RECIST v1.1) are eligible. The open-label Phase 2 randomizes patients to oral navtemadlin at a dose of 180 mg or 240 mg QD (Day 1–7/28-day cycle), or observation; primary endpoint is recommended Phase 3 dose (RP3D). The double-blind Phase 3 will randomize patients (2:1) to the RP3D vs placebo QD (Day 1–7/28-day cycle); stratification is by response and disease stage. Primary endpoint for Phase 3 is PFS by blinded independent review.Current Trial StatusThis study is now open to enrollment.Abstract TP008/#1500 Figure 1Study schema of KRT-232–118[Figure omitted. See PDF]