This trial of HST-1011 will evaluate the safety, tolerability, pharmacokinetics, harmacodynamics, and preliminary clinical activity of the agent when administered as a monotherapy or in combination with cemiplimab.
Trial Name: An Open Label, Phase 1/2 Study of HST-1011 Given as Monotherapy and in Combination With an Anti-PD1 Antibody in Patients With Advanced Solid Tumors
ClinicalTrials.gov Identifier: NCT05662397
Sponsor: HotSpot Therapeutics, Inc
Recruitment Contact: HotSpot Therapeutics, +1 (617) 758-8998, Clin001_Information@hotspotthera.com
Completion Date: December 31, 2026
The first patient has been dosed with HST-1011 in a phase 1/2 trial (NCT05662397) evaluating the agent in patients with advanced solid tumors, according to HotSpot Therapeutics, Inc.1
"Dosing of the first patient with HST-1011 is an important milestone for HotSpot signifying our evolution into a clinical-stage company with the first-in-human dosing of a product candidate derived from our proprietary Smart Allostery™drug discovery platform," said Tim Reilly, PhD, chief development officer of HotSpot. "Importantly, we believe that HST-1011, as a highly potent and selective inhibitor of the long sought after target CBL-B, may represent an important new immunotherapy treatment option for patients [with cancer]."
HST-1011 is an orally bioavailable, potent, selective small molecule allosteric inhibitor of casitas B-lineage lymphoma-B (CBL-B). The function of CBL-B is to act as a master regulator of effector cell immunity. As a result, its inactivation removes its endogenous negative regulatory functions to substantially enhance anti-tumor immunity.
In preclinical models, HST-1011 has shown the ability to bind to and inhibit a natural hotspot on CBL-B, yielding the activation and propagation of a targeted anti-tumor immune response. HST-1011 is designed with tight binding, low nanomolar potency, a slow dissociation rate from the target to enable sustained pharmacology, and greater selectivity for CBL-B relative to C-CBL.
In the phase 1/2 study, investigators are evaluating the safety, tolerability, pharmacokinetics, pharmacodynamics, and preliminary clinical activity of HST-1011 when administered to patients as monotherapy and in combination with the anti-PD-1 therapy, cemiplimab (Libtayo) in patients with advanced solid tumors.2
In phase 1 of the study, HST-1011 will be given to patients as either monotherapy in parts A1 and A2, or in combination with cemiplimab in part B. Part A1 consists of the monotherapy dose-escalation phase of the trial where cohorts of patients will be administered increasing doses of HST-1011. When part A1 is complete, an HST-1011 monotherapy dose optimization will commence, also known as part A2.
Then, part B is the dose-escalation part of the study where c will be given in combination with the standard dose or regimen of cemiplimab. Dosing in Part B may commence prior to the completion of Part A1.
In phase 2 of the study, investigators will assess the preliminary antitumor activity of HST-1011 in combination with anti-PD(L)1 antibody or other standard of care therapies.
Primary end points of the study are to evaluate the safety and tolerability in part A1 and to determine the recommended phase 2 dose of HST-1011 in part A2. Secondary end points include to evaluate the safety and tolerability of single-agent HST-1011 in part A2, pharmacokinetics, pharmacodynamics, overall response rate, duration of response, disease control rate, progression-free survival, and overall survival.
The trial plans to enroll approximately 203 patients who are at least 18 years of age or older, with a histologically confirmed, advanced solid tumor in 1 of the following categories: anti-PD-(L)1 relapsed/refractory; platinum-resistant ovarian cancer; anal cancer; rectal cancer; or castration-resistant prostate cancer.
Patients must have also failed prior standard of care therapies appropriate for their metastatic disease, have at least 1 measurable non-central nervous system lesions per RECIST 1.1, provide consent for pre- and on-treatment biopsies, and have an ECOG performance status of 0-1 to be eligible for enrollment in the study.
"Despite tremendous progress in the field of immuno-oncology [I-O], significant unmet need persists for patients with advanced solid tumors, as many cancers are found to be unresponsive to or lack durable responses following treatment with currently available therapies," said Jason Luke, MD, FACP, director of the Immunotherapy and Drug Development Center at the University of Pittsburgh Medical Center's Hillman Cancer Center and the lead principal investigator of the phase 1/2 clinical study.1 "We believe CBL-B's role as a master regulator of immune cell activation presents a differentiated therapeutic opportunity. We are excited to explore this novel mechanism and new I-O treatment in collaboration with HotSpot and the other investigators and sites participating in this trial."
