A Phase 1/2, open label dose-escalation and expansion trial of NKT2152, an orally administered HIF2α inhibitor, to investigate safety, PK, PD and clinical activity in patients with advanced ccRCC

Background: Inactivation of the VHL gene leading to aberrant HIF2α activity is nearly universal in clear cell renal cell carcinoma (ccRCC). NKT2152 is a novel, potent, selective orally available HIF2α inhibitor optimized for enhanced PK exposure and sustained target inhibition which has demonstrated robust activity in both ccRCC cell line-derived and patient-derived xenograft RCC and other solid tumor models. This is a Phase 1/2 open label, multicenter, first in human study of NKT2152 in adults with advanced clear cell renal cell carcinoma (ccRCC) (NCT05119335). In Phase 1, up to ~60 patients will be enrolled according to a 3 + 3 design with backfill as permitted by the Safety Review Committee. The primary objective of phase 1 is to determine the recommended dose for expansion (RDE) based on the totality of clinical data. Phase 2 will enroll ~50 additional patients with the primary objective of determining investigator-assessed by RECIST v1.1. Key secondary objectives include safety, tolerability, PD effects, progression free survival, duration of response, and disease control rate. Exploratory objectives include evaluation of biomarkers predictive of tumor response. Adults who have advanced ccRCC without available standard therapy), ECOG PS 0-2, with measurable disease per RECIST 1.1 are eligible. Patients who have had prior HIF2a inhibitors, require supplemental oxygen, and with significant cardiac disease are excluded. Tumor assessments by CT or MRI are conducted every 8 weeks until 48 weeks, then every 12 weeks thereafter. Adverse events will be monitored and graded in severity using CTCAE v5.0. The Phase 1 study is currently actively accruing in the United States with Phase 2 dose expansion anticipated to start in Q3, 2023.