Kpg-818, a novel cereblon (CRBN) modulator, in patients with hematological malignancies: Results of a Phase 1, open-label, multiple ascending dose study

Abstract Introduction: KPG-818 is a novel CRL4-CRBN E3 ubiquitin ligase modulator that binds to CRBN with high affinity and leads to rapid and effective degradation of Aiolos (IKZF3) and Ikaros (IKZF1), the transcription factors that play critical roles in B cell development and proliferation. KPG-818 is currently in development for the treatment of hematological malignancies and systemic lupus erythematosus. This Phase 1 study (NCT04283097) evaluated the safety, tolerability, pharmacokinetics (PK), and preliminary efficacy of KPG-818 in combination with dexamethasone (Dex) in adult patients (pts) with relapsed or refractory multiple myeloma (RRMM), or as monotherapy in pts with other selected hematological malignancies. Methods: The study was an open-label, multicenter, multiple-dose escalation study. Pts relapsed from or refractory to all FDA approved therapies unless the pts were not eligible for the approved therapy, with measurable diseases, and ECOG performance status score ≤1 were enrolled in the study. Pts with RRMM received at least 3 prior anti-myeloma regimens including at least 2 consecutive cycles of lenalidomide, pomalidomide, a proteasome inhibitor, a glucocorticoid and an anti-CD38 antibody. Oral KPG-818 was given daily at escalation doses of 2 or 5 mg on days 1-21 of each 28-day cycle，or 2 or 3 mg on days 1-10 of each 17-day cycle in combination with Dex at doses of 20-40 mg weekly in RRMM pts. Pts would be treated for 6 cycles, additional 6 cycles was allowed per discretion of the investigator. Results: A total of 18 pts (17 RRMM, 1 indolent lymphoma) received KPG-818: 15 (83.3%) were White, 13 (72.2%) were male, median age was 74 y (range: 59-83), median time since initial diagnosis was 6.8 y (range: 1.2-16.8), median number of prior systemic regimens was 6.5（range: 2-12), pts with prior autologous stem cell transplantation was 11 (61.1%). Overall, 17/18 (94.4%) pts experienced at least one treatment emergent adverse event (TEAE), and 15 (83.3%) had at least one grade 3/4 TEAE. There was no death in the study. The most common TEAE (more than 3 pts) was neutrophil count decrease, which was reversible. No pt experienced febrile neutropenia while on study. For 21 days on and 7 days off (21+7) schedule, 4 pts (1 in 2 mg, 3 in 5 mg) experienced dose-limiting toxicities (DLT). For 10 days on and 7 days off (10+7) schedule, no DLT occurred in 2 mg cohort; 2 pts in 3 mg experienced DLTs which were also the only treatment-related serious adverse events, one pneumonia and one thrombocytopenia. Based on these results, the maximum tolerated dose was exceeded. The most common DLT was neutrophil count decrease, which occurred in all 4 pts who experienced DLTs with 21+7 schedule and none in the 10+7 schedule. No treatment emergent peripheral neuropathy occurred during the study. Overall response rate (≥ partial response) and disease control rate (≥ stable disease) in the heavily treated patients with RRMM were 50% (3/6) and 83.3% (5/6) in 2 mg (10+7) cohort, 33.3% (1/3) and 100% (3/3) in 3 mg (10+7) cohort, 66.7% (2/3) and 100% (3/3) in 2 mg (21+7) cohort, and 50% (2/4) and 100% (4/4) in 5 mg (21+7) cohort, respectively. Over the dose range 2 to 3 mg in the 17-day dosing cycle or 2 to 5 mg in the 28-day dosing cycle, geometric mean AUCtand Cmax of KPG-818 generally appeared to increase in a dose proportional or slightly supra proportional manner, T1/2 of approximately 11 hours, and steady state was achieved by approximately Day 8. Conclusions: KPG-818 2 mg (10+7) showed promising efficacy and well tolerated safety profile in the heavily treated patients with RRMM. No new safety signals were identified. The 2 mg was selected as RP2D. Further clinical development of KPG-818 in RRMM is warranted.