KPG-121, a novel cereblon modulator, in patients with metastatic castration resistant prostate cancer: Results of a phase I multiple ascending dose study.
Authors: Michael Edward Devitt, Richard Michael Zuniga, Alfredo Torres, H. Keshava Prasad, Baisong Liao, Yao Wang
Journal: Journal of Clinical Oncology (2024)

e17054 Background: New treatments are needed for prostate cancer patients (pts) reaching the metastatic castration-resistant (mCRPC) stage of the disease. KPG-121 is a novel lenalidomide analogue that binds to CRL4-Cereblon (CRBN) with stronger interaction with CRBN, enhanced immunomodulatory activity, and greater anti-proliferative/anti-angiogenic properties when compared to lenalidomide. KPG-121 demonstrated synergy when combined with abiraterone, enzalutamide, apalutamide, and darolutamide in vitro and in vivo in preclinical studies. The KPG-121 first-in-human Phase 1 study evaluated the safety, pharmacokinetics (PK), and preliminary efficacy of KPG-121 plus enzalutamide, abiraterone, or apalutamide in mCRPC pts. Methods: This multicenter, open label, standard 3+3 dose ascending study was conducted in the United States. Eligible male adult pts with CRPC receiving stable doses of enzalutamide or abiraterone were given oral KPG-121 (1.5 mg, 2.5 mg, 5 mg, or 10 mg) once daily in 28-day (d) treatment cycles (21-d on and 7-d off or 10-d on and 4-d off 2 times). The primary endpoint was safety including treatment-emergent adverse events (TEAEs), dose-limiting toxicity, and maximum tolerated dose. Results: A total of 16 adult CRPC pts were enrolled to receive KPG-121. The mean age was 70.4 yrs with 12 pts (75%) being White, 2 pts (12.5%) being Black/African American, and 2 pts (12.5%) being of other races. All pts had mCRPC and received prior stable treatment of abiraterone or enzalutamide. A total of 12 pts (75.0%) had 88 TEAEs that were assessed by the Investigator as related to the study drug. The most commonly reported (≥ 2 pts) related AEs were neutropenia (9 [56.3%]), WBC count decreased (7 [43.8%]), platelet count decreased (6 [37.5%]), anemia (4 [25.0%]), thrombocytopenia (3 [18.8%]), lymphocyte count decreased (2 [12.5%]), electrocardiogram QT prolonged (2 [12.5%]), and muscle spasm (2 [12.5%]). A total of 5 pts (31.3%) who discontinued treatment due to TEAEs (2 in 2.5 mg, 1 in 5 mg, and 2 in 10 mg). One pt died due to COVID-19 assessed by the Investigator as not related to the study drug. Eight Serious Adverse Events (SAEs) were reported in 5 pts (31.3%) of which 1 SAE (neutropenia) was assessed by the Investigator as definitely related to the study drug. Of the 8 pts with RECIST evaluable disease, 3 pts (37.5%) had Partial Response and 3 pts (37.5%) had Stable Disease. Overall, Objective Response Rate and Disease Control Rate was 37.5% (3/8 pts) and 75.0% (6/8 pts), respectively. The PK evaluation of KPG-121 demonstrated dose-proportionality among the cohorts with t 1/2 ranging from 2.66 to 2.83 hrs. Conclusions: KPG-121 1.5 mg and 2.5 mg were generally well tolerated and showed meaningful clinical activity based on the preliminary efficacy data in mCRPC pts. Further evaluation of KPG-121 plus abiraterone, enzalutamide or other new hormone therapy is warranted. Clinical trial information: NCT03569280 .