70A phase 1 clinical trial of the farnesyltransferase inhibitor KO-2806 in combination with cabozantinib in renal cell carcinoma

Abstract Background Farnesyltransferase inhibitors (FTIs) block post-translational modification of RAS and other farnesylated proteins. HRAS-driven tumors are highly sensitive to FTI treatment. Recent clinical trials (NCT03719690, NCT02383927) of the FTI tipifarnib in patients with HRAS-mutant (HRAS-m) head and neck squamous cell carcinoma harboring high variant allele frequency mutations (VAF ≥20%) showed objective response rates of up to 50% and favorable long-term outcomes. KO-2806 is a next-generation FTI that has increased potency and improved pharmacokinetic properties. Furthermore, in preclinical studies, KO-2806 has been shown to enhance tumor growth inhibition of tyrosine kinase inhibitors, including cabozantinib, in multiple clear cell (cc) renal cell carcinoma (RCC) cell line- and patient-derived xenograft models. These preclinical data support clinical investigation of KO-2806 in combination with cabozantinib in RCC. Methods FIT-001 is an ongoing first-in-human, multicenter, open-label Phase 1a/b clinical trial evaluating the safety, tolerability, pharmacokinetics, pharmacodynamics (PD), and preliminary antitumor activity of KO-2806 as monotherapy or in combination therapy in advanced solid tumors (NCT06026410; Figure). Up to 270 patients will be enrolled in Phase 1a and Phase 1b combined across approximately 50 sites. Phase 1a has separate monotherapy and combination dose-escalation arms. KO-2806 in combination with cabozantinib is being evaluated in RCC. Patients with advanced or metastatic ccRCC who progressed on ≥ 1 prior line of immunotherapy-based systemic therapy and patients with non-ccRCC who are treatment-naïve or who received any prior systemic therapy are eligible. On the basis of emerging data from Phase 1a, two PD cohorts (n ≤ 12) with mandatory pre- and on-treatment tumor biopsies may be enrolled. In Phase 1b dose expansion, patients will receive the recommended phase 2 dose (RP2D) of KO-2806 with cabozantinib or will be randomized by dose if two potential KO-2806 RP2Ds are identified for the combination. The study began accrual in October 2023, and recruitment is ongoing. Significance & Vision FIT-001 is assessing the safety, tolerability, pharmacokinetics, PD, and preliminary antitumor activity of KO-2806 in combination with cabozantinib in patients with ccRCC and non-ccRCC. Trial Schema