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#84 Trial in progress: a phase 2/3 study of navtemadlin as maintenance therapy in patients with advanced or recurrent endometrial cancer (EC) who responded to chemotherapy (ENGOT-En21 and GOG-3089)
  1. Nicole Concin1,
  2. Ugo De Giorgi2,
  3. Toon Van Gorp3,4,
  4. Jérôme Alexandre5,
  5. Kristina Lindemann6,7,
  6. Christian Marth1,
  7. Regina Berger1,
  8. David Cibula8,
  9. María Quindós9,
  10. Alessandra Bologna10,
  11. Jacob Korach11,
  12. Christos Papadimitriou12,
  13. Shibani Nicum13,
  14. Dearbhaile Collins14,
  15. Reg Myers15,
  16. Wayne Rothbaum15,
  17. Thomas J Herzog16,
  18. Bradley J Monk17 and
  19. Noelle Gillette Cloven18
  1. 1Medical University of Innsbruck, Univ-Clinic for Gynecology and Obstetrics, Innsbruck, Austria and AGO (Arbeitsgemeinschaft für gynäkologische Onkologie), Innsbruck, Austria
  2. 2IRCCS Istituto Romagnolo per lo Studio dei Tumori (IRST) Dino Amadori, Meldola, Italy
  3. 3University Hospital Leuven, Leuven Cancer Institute, Leuven, Belgium
  4. 4Luxembourg Gynaecological Oncology Group (BGOG), Leuven, Belgium
  5. 5Université de Paris Cité, Hôpital Cochin, Paris, France
  6. 6Oslo University Hospital, The Norwegian Radium Hospital, Oslo, Norway
  7. 7Institute of Clinical Medicine, University of Oslo, Oslo, Norway
  8. 8General University Hospital in Prague, First Faculty of Medicine, Charles University, Prague, Czech Republic
  9. 9Complexo Hospitalario Universitario de A Coruña. Biomedical Research Institute (INIBIC), A Coruña, Spain
  10. 10Azienda Unità Sanitaria Locale di Reggio Emilia-IRCCS, Reggio Emilia, Italy
  11. 11Sheba Medical Center, Ramat Gan, Tel Aviv, Israel
  12. 12Aretaieion University Hospital, National and Kapodistrian University of Athens, Athens, Greece
  13. 13University College London, London, UK
  14. 14Cork University Hospital, Cork, Ireland
  15. 15Kartos Therapeutics Inc., Redwood City, USA
  16. 16University of Cincinnati Cancer Center, Cincinnati, USA
  17. 17HonorHealth Research Institute, University of Arizona, Creighton University, Phoenix, USA
  18. 18Texas Oncology-Fort Worth Cancer Center, Fort Worth, USA


Introduction/Background Advanced/recurrent EC has poor prognosis with 5-year survival rate of ~17% (Colombo 2016; Siegel 2022). Maintenance treatment may improve and extend the durability of response to initial chemo/chemoimmunotherapy; novel agents are being tested in this setting to improve survival outcomes.

The tumor suppressor protein p53 can detect intracellular DNA damage and oncogenic aberrations leading to orderly apoptosis of tumorigenic cells. Mouse double minute 2 (MDM2), the key negative regulator of p53, is upregulated by some cancers to prevent p53 tumor suppressor function, while other cancers inactivate p53 by direct loss or mutation. MDM2 is upregulated in ~50% of EC patients (Jeczen 2007) due to loss of p14ARF, a critical modulator of intranuclear MDM2 levels.

Navtemadlin is a potent, selective, orally available MDM2 inhibitor that restores p53-mediated apoptosis in TP53WT tumors. The sensitivity of EC to genotoxic chemotherapy (Miller 2020) suggests susceptibility to p53-mediated apoptosis. Post-chemotherapy maintenance treatment with navtemadlin may provide a non-genotoxic way to maintain p53-driven activity and tumor cell control in the ~50% of EC patients who are TP53WT (Nakamura 2019).

KRT-232–118 is a Global 2-part Phase 2/3 study evaluating the safety and efficacy of navtemadlin as maintenance therapy in TP53WT advanced/recurrent EC patients following response to chemotherapy (EudraCT 2022–5002196-31; NCT05797831).

Methodology Eligible patients are adults with ECOG PS 0–1 who completed up to 6 cycles of chemotherapy excluding adjuvant/neo-adjuvant therapy and achieved CR or PR per RECIST v1.1. The open-label Phase 2 randomizes patients 1:1:1 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 progression-free survival by blinded independent review.

Results NA

Abstract #84 Figure 1

Study schema of KRT-232–118

Conclusion NA

Disclosures Funded by Kartos Therapeutics Inc.

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