Safety, pharmacokinetics (PK), pharmacodynamics (PD) and efficacy of KT-253, a targeted protein degrader of MDM2, in patients with relapsed/refractory (R/R) solid tumors, lymphoma, high grade myeloid malignancies and acute lymphoblastic leukemia (ALL).
Authors: Khawaja M. Rizwan Rizwan-ul-Haq , Naqash Abdul Rafeh , Schneider Reva , Shastri Aditi , Stahl Maximilian , Moser Justin C , Abdel Karim Nagla Fawzy , Madanat Yazan , Jonas Brian Andrew , Stein Eytan , Gadgeel Shirish M. , McCloskey James K. , Gollerkeri Ashwin , Perea Rachelle , Chutake Yogesh , Agarwal Sagar , Henrick Patrick , Shi Kelvin , Daver Naval Guastad 
Published: July 2024

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Background: The tumor suppressor p53 is mutated in approximately 50% of cancers. In those cancers with wild-type p53, its activity is controlled by mouse double minute 2 (MDM2), an E3 ligase that tags p53 for degradation. KT-253 is a novel, highly potent heterobifunctional MDM2 degrader that upregulates p53 activity and overcomes the p53-MDM2 feedback loop, resulting in >200-fold higher potency compared to MDM2 inhibitors. In preclinical PDX models of sensitive p53WT solid tumors, AML and ALL, KT-253 robustly activates p53, induces apoptosis, and results in tumor regressions with every 3-week dosing. The ability to rapidly induce an acute apoptotic response and dose intermittently may result in a therapeutic index that has eluded previous MDM2 targeting agents. Methods: The ongoing open-label Phase 1 study evaluates safety, PK, PD and preliminary efficacy of IV KT-253 administered on Day 1 of 21-day cycles. Patients (pts) with advanced (≥2 prior therapies) solid tumors (ST)/lymphomas (Arm A) and relapsed/refractory (R/R) high grade myeloid malignancies (AML, high/very-high risk myelodysplastic syndrome (MDS), MDS/myeloproliferative neoplasms) and ALL (Arm B) are eligible. Blood samples are collected for KT-253 PK/PD analyses. Results: As of 26 January 2024, 18 pts have been treated, 13 in Arm A dose levels (A: DL) 1-4 and 5 in Arm B dose levels (B: DL) 1-2, with mean number of 3 and 2 doses, respectively. The most common solid tumor types were Merkel cell carcinoma ((MCC) n=3), adenoid cystic carcinoma ((ACC) n=2) and uveal melanoma (n=2). Arm B included 5 pts with R/R AML. The median age was 61 years (yrs) (range 42, 81) in Arm A and 66 yrs (range 57, 70) in Arm B. The most common adverse events (AEs) in > 20% of pts included nausea, fatigue, headache, and vomiting. There was 1 DLT of AEs leading to discontinuation that included Grade (G) 2 nausea and fatigue in A: DL4. There were no neutropenia or thrombocytopenia AEs in either arm. KT-253 related SAEs included G3 hypotension in a pt with decreased oral intake (A: DL1). Overall best response: 1 CR (B: DL2, AML); 2 PRs (A: DL1, MCC; B: DL1, AML); 3 SD (A: DL1, fibromyxoid sarcoma; DL2, ACC; DL3, renal cell cancer). PD data from A: DL1-4 and B: DL1-2 demonstrated rapid upregulation of plasma GDF-15 protein and upregulation of CDKN1A and PHLDA3 mRNA levels in blood. KT-253 demonstrated dose-dependent increase in plasma exposure with levels approximating efficacious doses. Conclusions: KT-253 results in potent upregulation of p53-dependent biomarkers and has demonstrated early signs of anti-tumor activity including objective responses in MCC and AML at doses that are well tolerated. Dose escalation is ongoing at DL4 in Arm A and at DL2 in Arm B and analyses from additional pts will be presented at the meeting. Clinical trial information: NCT05775406 .