Abstract CT251: Phase 1/2 study of HST-1011, an oral CBL-B inhibitor, alone and in combination with anti-PD1 in patients with advanced solid tumors
Authors: Luke Jason , Sanborn Rachel E. , Rodón Jordi , Patel Manish , Agarwal Parul , Friedman Evan , Peterson Connacht , Kelley Heather , Wright Emma , Danaee Hadi , Sun Huadong , Barth Carolin , Reilly Timothy , Redig Amanda J. , Friedman Claire 
Published: April 2023

Abstract
Background: The E3 ligase Casitas B-lineage lymphoma proto-oncogene B (CBL-B) is a master negative regulator of the immune system and thus an attractive target to address suboptimal outcomes to immune checkpoint inhibitors (ICI). CBL-B controls T-cell/NK cell activation and co-stimulatory pathways, including the signaling threshold for T-cell receptor (TCR) activation. CBL-B inhibition uncouples TCR stimulation from the requirement for CD28 co-stimulation while reducing T-cell susceptibility to immunosuppression mediated by PD1, immunosuppressive cytokines, and Treg cells. Accordingly, targeting CBL-B may enable immune activation even in tumors with low antigen levels, low intratumoral inflammation, inadequate co-stimulation and/or active immunosuppression associated with poor response/resistance to existing ICIs. HST-1011 is a novel, potent, selective, orally bioavailable allosteric small molecule CBL-B inhibitor that has been shown to robustly increase anti-tumor immunity in vitro and in vivo, including in model systems where other ICIs have minimal effect.
Methods: SOLAR1 (NCT05662397) is a first-in-human, multicenter Ph1/2 trial investigating safety and tolerability (primary endpoint), pharmacokinetics (PK), pharmacodynamics (PD), and preliminary efficacy (secondary endpoints) of HST-1011 monotherapy and an HST-1011/PD1 inhibitor combination. HST-1011 will be given orally while the PD1 inhibitor cemiplimab will be administered intravenously.
Eligibility: Patients with advanced solid tumors and progression on standard of care diagnosed with a) tumor types for which PD-(L)1 therapies are approved with documented PD-(L)1 refractory/resistant disease, including patients with best response of stable disease for ≥ 6 months while on a PD-(L)1, OR b) selected tumor types in which patients may be naïve to anti-PD(L)1 (platinum-resistant ovarian cancer, metastatic castration-resistant prostate cancer without bony lesions, rectal cancer, anal cancer).
Study Design: Ph1, Part A1: HST-1011 monotherapy dose escalation, utilizing a Bayesian optimal interval design (BOIN). Optional dosing cohorts will assess alternative dosing strategies. Ph1, Part A2: HST-1011 monotherapy dose optimization with up to 4 cohorts utilizing dose(s)/schedule(s) deemed safe in Part A1 but focused on histology-specific patient populations to generate additional PK, PD, and efficacy data within a potential Recommended Phase 2 Dose (RP2D) range. Ph1, Part B: HST-1011 dose escalation in combination with cemiplimab, as in Part A1 with a BOIN design and optional dosing cohorts.
Biomarkers: Target engagement and PD will be assessed via a) serial monitoring of cytokines/chemokines and transcriptional profiles; b) peripheral immune cell profiling; and c) in-depth analysis of screening and on-treatment tumor biopsies. The study is open with competitive enrollment.
Citation Format: Jason Luke, Rachel E. Sanborn, Jordi Rodón, Manish Patel, Parul Agarwal, Evan Friedman, Connacht Peterson, Heather Kelley, Emma Wright, Hadi Danaee, Huadong Sun, Carolin Barth, Timothy Reilly, Amanda J. Redig, Claire Friedman. Phase 1/2 study of HST-1011, an oral CBL-B inhibitor, alone and in combination with anti-PD1 in patients with advanced solid tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr CT251.