KPG-121, a novel cereblon modulator, in patients with metastatic castration resistant prostate cancer: Results of a phase I multiple ascending dose study.

person Michael Edward Devitt University of Virginia Comprehensive Cancer Center, Charlottesville, VA info_outline Michael Edward Devitt, Richard Michael Zuniga, Alfredo Torres, H. Keshava Prasad, Baisong Liao, Yao Wang

Authors person Michael Edward Devitt University of Virginia Comprehensive Cancer Center, Charlottesville, VA info_outline Michael Edward Devitt, Richard Michael Zuniga, Alfredo Torres, H. Keshava Prasad, Baisong Liao, Yao Wang Organizations University of Virginia Comprehensive Cancer Center, Charlottesville, VA, New York Cancer and Blood Specialists, Port Jefferson Station, NY, Comprehensive Cancer Centers of Nevada, Las Vegas, NV, Kangpu Biopharmaceuticals, Ltd, Shanghai, China Abstract Disclosures Research Funding No funding sources reported 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.

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