Bexon Clinical Consulting (United States)

Abstract Background: Based on its single-agent clinical activity and excellent safety profile, OR502 has best-in-class properties. Preclinically, OR502 reverses and prevents myeloid cell-mediated immune suppression and restores T cell functions with superior activity than other antibodies targeting LILRB2. OR502 binds to a distinct epitope of LILRB2, and blocks more broadly LILRB2 binding to its ligands. In addition, OR502 co-engages activating FcγR on myeloid cells. Here we report pharmacokinetic (PK) and receptor occupancy (RO) data from a phase 1 study [NCT06090266] dose escalation cohorts in patients with refractory solid tumors. Methods: Primary objectives included selection of an OR502 dose for the next stage of study, supported by LILRB2 RO and PK in addition to safety and efficacy. OR502 was given IV in 21-day (D) cycles (C) in 5 cohorts from 100-1600 mg in 2 separate escalations: monotherapy (mono) or + standard dosing of cemiplimab (combo). Serial PK sampling was performed during C1 and C3, then D1 every other C. Peripheral RO was assessed weekly during C1 and C3 and on D1 of C2 and C4 by flow cytometry. An OR502 anti-idiotype was used to measure OR502 bound to LILRB2 on the surface of myeloid cells vs unoccupied and total LILRB2 before and after OR502 administration. PK data were analyzed using PKanalix®. Results: Table summarizes patient characteristics, PK and RO from mono and combo escalation cohorts. Conclusions: OR502 PK and RO support Q3W dosing, and based on near-complete RO and predictable PK, justify the OR502 dose selected for mono and combo expansion cohorts of 800 mg IV Q3W in PD-(L)1 pretreated cutaneous melanoma and NSCLC, respectively. Citation Format: Andrae Vandross, David Sommerhalder, Mohamad Salkeni, Damien Cronier, Myriam N. Bouchlaka, Kamal Puri, Nenad Sarapa, Lesley Skingley, Mike Yefimenko, Alice Bexon, Shiraj Sen. Clinical pharmacokinetics and peripheral receptor occupancy of OR502, best-in-class antibody against leukocyte immunoglobulin-like receptor B2 (LILRB2), alone and in combination with cemiplimab [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_2):Abstract nr LB299.

Abstract BACKGROUND C/EBPβ is a transcription factor that is active during embryofetal development but held in an inactive state in most mature cells (Zahnow 2009). C/EBPβ is upregulated or overactivated in multiple cancers, where it inversely correlates with disease prognosis and survival due to activation of a gene signature that promotes tumor cell proliferation and survival. ST101 is a cell-penetrating peptide antagonist of C/EBPβ. ST101 exposure leads to selective tumor cell death in multiple human cancer cell lines, including GBM, without impacting normal cell viability. In vivo, ST101 displays rapid uptake into multiple organs, the ability to cross the blood-brain barrier, and a long plasma half-life due to its resistance to degradations. It has potent anti-tumor activity in multiple GBM models, as a single agent or in combination, which supported moving into clinical development. TRIAL DESIGN This phase 1-2 study is enrolling patients ≥ 18 years of age with advanced, unresectable metastatic solid tumors refractory to or intolerant of other therapeutic options. We began recruitment in August 2020. The primary objective of phase 1 is to evaluate safety and tolerability of ST101. Secondary objectives include the recommendation of a dose and regimen of ST101 for further evaluation, pharmacokinetics, several pharmacodynamic measures, and preliminary efficacy. Patients receive intravenous ST101 once weekly in a standard 3 + 3 design. Enrollment is ongoing, and by 21 May 2021, 15 patients have been recruited in four dose-escalation cohorts up to 4 mg/kg; a 5th cohort (6 mg/kg) is ongoing. The recommended phase 2 dose will be used in a 15-30 patient GBM expansion cohort, with a Simon 2-stage design, which requires one response or two patients with PFS6 in the first cohort to continue the study. Up to 120 patients are planned in a total of four expansion cohorts, which should be enrolling by Q3 2021.

Abstract Background: AST-008 is a novel spherical nucleic acid configuration of a toll-like receptor 9 (TLR9) agonist oligonucleotide, designed to trigger anti-tumor immune responses. Here we focus on immune activation upon AST-008 injection in the phase 1b/2 study in patients with advanced solid tumors (NCT03684785). Materials and Methods: AST-008 was injected intratumorally (IT) into one or more tumors QW for 8 doses, then Q3W thereafter, at doses from 2 to 32 mg. Starting at week 3, pembrolizumab was administered per label until toxicity or progression. Peripheral blood immune cell profiling and cytokine/chemokine analyses were performed before and 24 hours after both the first AST-008 dose (week 1) and the first combination dose (week 3). Serial tumor biopsies of lesions were collected from both AST-008-injected lesions and non-injected (“witness”) lesions at baseline, after IT AST-008 monotherapy, and after combination therapy. Results: Seventeen patients have been enrolled in the dose escalation cohort: median age 66 [range: 30-86], 82% male, median ECOG 1 [0-1]. Dose dependent lymphocyte activation was observed after IT AST-008. AST-008 dosing alone (16 mg cohort, n = 3) increased activated fractions of CD4+ (33%) and CD8+ T cells (64%), monocytes (97%) and NK cells (94%), compared to baseline (15%, 22%, 4%, and 37%, respectively). At AST-008 doses of 8 and 16 mg, the cell activation response within a dose level was generally similar in the presence or absence of pembrolizumab. In addition, the cytokines/chemokines IL-12p40, IL-1RA, IP-10, and MCP-1 were induced in a dose-proportional manner after IT AST-008 mono- or combination therapy. IT AST-008 resulted in average fold increase of 5, 12, and 16 for doses of 2, 4, and 8 mg dose cohorts, respectively, in IP-10 concentration from baseline (n = 11). Generally, combination therapy with pembrolizumab and AST-008 at doses of 2 and 4 mg produced a cytokine/chemokine response that was smaller than AST-008 alone (n = 5), but 8 mg dose responses were similar after monotherapy or combination therapy (n = 3). Preliminary analysis of serial biopsies by Nanostring revealed increased T cells and cytotoxic cells in the injected lesion after AST-008 dosing (n = 4) and in the non-injected witness lesion after combination therapy (n = 6). Combination therapy produced increases in B cells, T cells, cytotoxic cells and macrophages the AST-008 injected lesions (n = 6). Further PD data are being collected. The emerging safety profile consists mostly of grade (G) 1 and 2 injection site reactions and flu-like symptoms, reflecting local and systemic immune activation. One G3 lymphocytopenia has been observed, with no clinical consequences. No AST-008-related serious AEs or DLTs have been reported. Conclusions: IT AST-008 is well tolerated at the doses administered and is associated with dose-proportional systemic immune activation. Gene expression analysis suggests increased lymphocytes in the injected tumor after IT AST-008 and in both injected and witness tumors after combination therapy. Citation Format: Mohammed M. Milhem, Cesar A. Perez, Glenn J. Hanna, Trisha M. Wise-Draper, Shailender Bhatia, Alice S. Bexon, Weston L. Daniel, Steven J. O'Day. Phase 1b/2 study of an intratumoral TLR9 agonist spherical nucleic acid (AST-008) and pembrolizumab: Evidence of immune activation [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr LB-140.

IntroductionOnapristone is a type I progesterone receptor (PR) antagonist, which prevents PR- mediated DNA transcription. Onapristone is active in multiple preclinical models and two prior studies demonstrated promising activity in patients with breast cancer. We conducted a study of extended release (ER) Onapristone to determine a recommended dose and explore the role of transcriptionally-activated PR (APR), detected as an aggregated subnuclear distribution pattern, as a predictive biomarker.MethodsAn open-label, multicenter, randomized, parallel-group, phase 1 study (target n = 60; NCT02052128) included female patients ≥18 years with PRpos tumors. APR analysis was performed on archival tumor tissue. Patients were randomized to five cohorts of extended release (ER) onapristone tablets 10, 20, 30, 40 or 50 mg BID, or immediate release 100 mg QD until progressive disease or intolerability. Primary endpoint was to identify the recommended phase 2 dose. Secondary endpoints included safety, clinical benefit and pharmacokinetics.ResultsThe phase 1 dose escalation component of the study is complete (n = 52). Tumor diagnosis included: endometrial carcinoma 12; breast cancer 20; ovarian cancer 13; other 7. Median age was 64 (36–84). No dose limiting toxicity was observed with reported liver function test elevation related only to liver metastases. The RP2D was 50 mg ER BID. Median therapy duration was 8 weeks (range 2–44), and 9 patients had clinical benefit ≥24 weeks, including 2 patients with APRpos endometrial carcinoma.ConclusionClinical benefit with excellent tolerance was seen in heavily pretreated patients with endometrial, ovarian and breast cancer. The data support the development of Onapristone in endometrial endometrioid cancer. Onapristone should also be evaluated in ovarian and breast cancers along with APR immunohistochemistry validation.