FDA approves phase 2/3 trial of KPG-121 plus abiraterone in mCRPC

The FDA has approved a phase 2/3 clinical trial of KPG-121 in combination with abiraterone acetate (Zytiga) for investigation in the first-line treatment of patients with metastatic castration-resistant prostate cancer (mCRPC).¹

“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," wrote the investigators.

KPG-121 is a novel lenalidomide analogue that binds to CRL4-Cereblon and targets “rapid ubiquitination and degradation of casein kinase 1α (CK1α) and transcription factors Aiolos (IKZF3) and Ikaros (IKZF1),” according to a news release from Kangpu Biopharmaceuticals, the developer of the therapy.¹

According to the news release, in preclinical studies, KPG-121 improved anti-tumor efficacy when combined with abiraterone, enzalutamide, apalutamide, and darolutamide in vitro and in vivo compared with KPG-121 alone.

Data from a phase 1 study (NCT03569280) of KPG-121 were also recently presented at the 2024 ASCO Annual Meeting in Chicago, Illinois.² The study evaluated the safety, pharmacokinetics, and preliminary efficacy of the therapy in combination with enzalutamide, abiraterone, or apalutamide in patients with metastatic CRPC or non-metastatic CRPC. Those included in the study received oral KPG-121 at the dose level of either 1.5 mg, 2.5 mg, 5 mg, or 10 mg, administered once daily in 28-day treatment cycles (with 21 days on and 7 days off or 10 days on and 4 days off 2 times).

In total, 88 treatment-emergent adverse events (TEAEs) were observed across 12 patients (75%) in the study. Additionally, 8 serious AEs were reported among 5 patients (31.3%), of which 1 (neutropenia) was determined by the investigator as definitely being related to the study drug.

AEs reported in 2 or more patients included neutropenia (56.3%), a decrease in white blood cell count (43.8%), a decrease in platelet count (37.5%), anemia (25.0%), thrombocytopenia (18.8%), a decrease in lymphocyte count (12.5%), electrocardiogram QT prolonged (12.5%), and muscle spasm (12.5%).

Among all patients, 5 patients (31.3%) discontinued treatment due to TEAEs, with 2 being in the 2.5 mg cohort, 1 in the 5 mg cohort, and 2 in the 10 mg cohort. Further, 1 patient in the study died due to COVID-19, which was not found to be related to the study drug.

Preliminary efficacy analyses of KPG-121 showed that of the 8 patients with RECIST evaluable disease, 3 patients (37.5%) achieved a partial response and 3 patients (37.5%) achieved stable disease. The objective response rate and disease control rate in the study were 37.5% and 75.0%, respectively.

An analysis of pharmacokinetics also showed dose-proportionality among the cohorts, with the t1/2 value ranging from 2.66 to 2.83.

Overall, the first-in-human, open-label, multicenter, phase 1 trial enrolled 16 adult patients with metastatic CRPC or non-metastatic CRPC across clinical trial sites in the United States. The mean age of participants was 70.4 years. All patients enrolled in the trial had received prior stable treatment with abiraterone or enzalutamide.

The primary end point for the trial was the determination of a maximum tolerated dose and a recommended phase 2 dose. Secondary end points included the incidence of AEs and the pharmacokinetics of KPG-121.³

The investigators concluded, “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.”

References

1. FDA approved phase II/III clinical study of KPG-121 in combination with abiraterone as a first line treatment for mCRPC. News release. Kangpu Biopharmaceuticals. June 5, 2024. Accessed June 6, 2024. https://www.biospace.com/article/releases/fda-approved-phase-ii-iii-clinical-study-of-kpg-121-in-combination-with-abiraterone-as-a-first-line-treatment-for-mcrpc/

2. Devitt ME, Zuniga RM, Torres A, et al. KPG-121, a novel cereblon modulator, in patients with metastatic castration resistant prostate cancer: Results of a phase I multiple ascending dose study. Presented at: 2024 American Society for Clinical Oncology Annual Meeting. May 31-June 4, Chicago, Illinois. Abstract e17054. https://ascopubs.org/doi/10.1200/JCO.2024.42.16_suppl.e17054

3. Evaluation of safety and efficacy of KPG-121 plus enzalutamide, abiraterone or apalutamide in CRPC patients. ClinicalTrials.gov. Last updated July 18, 2023. Accessed June 7, 2024. https://clinicaltrials.gov/study/NCT03569280