Journal Article

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

Kuan, J C, Singer, Adam E, Bendris, Nawal, Saunders, Andrew, Hanna, Glenn J, Dale, Stephen, Ayanambakkam, Adanma, Garmezy, Benjamin, Seraj, Jabed, Balsara, Binaifer, Patel, Manish R, Rosen, Lee S, Pelster, Meredith, Johnson, Paria Mahboub, Thomas, Jacob

2025

Overview

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

• Publisher: Oxford University Press
• Subject: Trials in Progress Posters