CCAAT/Enhancer Binding Protein β (C/EBPβ) is a basic leucine zipper (bZIP) transcription factor that causes aberrant gene expression in many cancers. Upregulated or overactivated C/EBPβ drives oncogenesis by promoting tumor survival and proliferation and is a critical regulator of the immunosuppressive tumor microenvironment (TME). Specifically, C/EBPβ regulates macrophage differentiation, activating a transcriptional program driving macrophage polarization toward immunosuppressive M2-type myeloid-derived suppressor cells (MDSCs). Consistently, activation of C/EBPβ correlates with poor prognosis in several types of human cancer. Thus, targeting C/EBPβ to reprogram tumor-associated macrophages (TAMs) from the M2 toward the immune-promoting M1 phenotype represents an attractive strategy to enhance antitumor immunity. ST101 is a novel peptide antagonist of C/EBPβ dimerization that inhibits C/EBPβ-dependent gene expression. Here we evaluated the impact of ST101 on macrophage differentiation, cytotoxic T-cell activation, and in vivo anti-tumor activity. Primary human macrophages cultured from Peripheral Blood Mononuclear Cells (hPBMCs) were activated toward the M1 or M2 phenotype by LPS and IFNγ or IL-4, respectively. ST101 exposure dose-dependently suppressed expression of M2 markers (CD163, CD206) while inducing M1 markers (CD80, CD86) by flow cytometry and quantitative PCR, resulting in a 40-fold increase in the M1/M2 ratio without substantial impact on cell viability. Next, in co-cultures of T cells with M2 macrophage, ST101 exposure resulted in a 4-fold increase in T-cell activation compared to control M2/T cell co-cultures, as measured by intracellular IFN-γ staining. Importantly, ST101 did not suppress proliferation or activity of T cells cultured alone. Finally, in an orthotopic TNBC model in vivo, ST101 in combination with anti-PD-1 treatment enhanced anti-tumor activity compared to either single agent alone. The observed increase in tumor growth inhibition was accompanied by a reduced TAM fraction and increased intratumoral and peripheral M1/M2 ratios. ST101 is being evaluated in a Phase 1-2 clinical study in patients with advanced unresectable and metastatic solid tumors (NCT04478279). Initial gene expression analysis performed on 8 paired patient biopsies (prior to ST101 exposure and within 24 hrs of ST101 administration during cycle 2 of therapy) collected during dose escalation (4 mg/kg ST101 or greater) indicates a significant decrease in expression of multiple factors involved in M2 polarization, including CD209, SIGLEC5 and IL-24, and T cell suppression, including FoxP3 and inhibitory KIR proteins. The result is a decrease in intratumoral regulatory T cell (Treg) vs. TIL ratio, indicating a shift towards a more immunoactive TME. Overall, these results support a novel, macrophage-driven mechanism of action for ST101 as anticancer agent and suggest the exploration of ST101 in immune-oncology therapeutic strategies. Citation Format: Claudio Scuoppo, Rick Ramirez, Siok Leong, Lila Ghamsari, Gina Capiaux, Rob Michel, Steve Kaesshaefer, Gene Merutka, Barry Kappel, Abi Vainstein-Haras, Alice Bexon, Jim Rotolo. ST101, a peptide antagonist of novel I/O target CEBPβ,reprograms MDSCs and promotes an immunoactive tumor microenvironment [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 LB236.
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 activates a proliferation/survival gene signature in multiple cancers, where it inversely correlates with disease prognosis 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 degradation. 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 2 study is enrolling adult patients with GBM that has recurred or progressed after one standard treatment regimen (surgery, radiotherapy +/-temozolomide). Patients require measurable disease at baseline and at least 3 months from prior radiotherapy. Subjects receive the recommended phase 2 dose of ST101 (500mg IV weekly). Recruitment in the phase 2 portion of this trial began in January, 2022. RESULTS As of June 1, 2022, 14 GBM patients were enrolled. One patient has a confirmed mRANO partial response (PR) after 18 weeks of therapy, seven patients have not reached the first on-study assessment and six patients progressed. The median duration of therapy was 5 weeks. ST101 has a favorable safety profile with minor infusion related reactions being the most common adverse event. Based on the confirmed PR, the GBM cohort will be expanded. CONCLUSION This first-in-class C/EBPβ inhibitor, ST101, showed an early signal of activity in recurrent GBM. More extensive follow-up and clinical experience will be presented as this trial expands and matures.
Background: Increased activation of transcription factor CCAAT/enhancer-binding protein β (C/EBPβ) promotes tumor survival and proliferation and inhibits differentiation. ST101 is a therapeutic peptide designed to antagonize C/EBPβ; it penetrates the blood-brain barrier and has anti-tumor activity in multiple human cancer cell lines and animal models. Methods: This was a first-in-human, open-label, phase 1-2 dose-finding study. The primary objective was to evaluate safety and tolerability in patients with cancer. Secondary and exploratory objectives included ST101 pharmacokinetics (PK) and pharmacodynamics (PD). Phase 1 enrolled patients with advanced/metastatic solid tumors refractory or intolerant to all therapeutic options. Patients received ST101 intravenously 0.5, 1, 2, 4, 8 mg/kg QW and 16 mg/kg Q2W in a standard 3+3 design. The recommended phase 2 dose will be further investigated in expansion cohorts of patients with breast cancer, melanoma, glioblastoma, and castration-resistant prostate cancer. Results: As of 01.05.21 9 patients have enrolled into phase 1. Patients received 1-5 prior lines of therapy and had an ECOG status of 0 or 1. PK was predictable and consistent with pre-clinical data. Mean Cmax and AUC(0-t) increased proportionally with increasing dose. Maximum concentrations were observed at the end of 90-minute infusion and mean T1/2 was calculated as 18h and 31h, respectively in Cohort 1 and Cohort 2. Concentrations of ST101 were similar on Days 8 and 15 when compared to Day 1 in each cycle. Immunohistochemistry of tumor samples taken shortly after the 4th infusion from 2/2 patients in Cohort 1 and 1/1 patient in cohort 2 stained positive for ST101. No ST101-related serious adverse events were observed. There were no dose limiting toxicities, dose modifications or withdrawals due to toxicity. Symptoms of infusion related reactions (max grade 2) were reported in five patients and were managed with antihistamine and/or anti-inflammatory prophylaxis and by decreasing the infusion rate. Five patients withdrew due to progression of their cancer. Conclusions: ST101 was safe and well tolerated at the doses and schedule tested, and PK appeared predictable. ST101 was designed to have a prolonged plasma T1/2 and these results confirm preclinical observations, demonstrating a longer than expected T1/2 for a drug of this class. Tumor uptake of ST101 was demonstrated at the lowest dose level. ST101 dose(mg/Kg)CyclenMean Cmax (ng/mL)Mean Tmax (h)Mean AUC(0-t)(h*ng/mL)Mean Tlast (h)Mean AUC(0-inf)(h*ng/mL)Mean T1/2(h)Mean extrapolation(%)0.51316001.59000271500018230.52214001.539006NDNDND0.53211339001.5390007245000311512148001.5180008NDNDND131 Citation Format: Gerald Falchook, Meredith McKean, Nehal Lakhani, Tobias Arkenau, Stefan Symeonides, Jeff Evans, Emerson Lim, Jim Rotolo, Rob Michel, Alice Bexon. Tumor uptake and predictable PK of ST101 - a peptide antagonist of C/EBPβ - in patients with advanced unresectable and metastatic solid tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr LB114.
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.
Introduction: The oncogenic transcription factor CCAAT/enhancer-binding protein β (C/EBPβ) is normally active in embryofetal development, but inactive and suppressed in mature cells. Upregulation or activation of C/EBPβ in cancer promotes tumor survival and proliferation while inhibiting its differentiation. ST101 is a peptide antagonist of C/EBPβ, with anti-tumor activity in glioblastoma (GBM), breast cancer (BC), prostate cancer (PC), melanoma, and other models. ST101 penetrates the blood-brain barrier, as demonstrated in a mouse model and biodistribution studies. We have also demonstrated the tumor-specificity of ST101 in numerous in vitro cell lines. Methods: We conducted the phase 1 portion of a phase 1-2 study in patients with refractory solid tumors. The primary objective was to evaluate safety and tolerability of ST101. Secondary and exploratory objectives included PK, preliminary efficacy, and PD from serial biopsies. The study used a 3+3 design, dosing ST101 IV at 0.5, 1, 2, 4, 6, and 8 (now modified to 9) mg/kg weekly (QW). Phase 2 will include four cohorts of patients with specific cancers: HR+ breast cancer, cutaneous melanoma, GBM, and castrate-resistant PC at the recommended phase 2 dose (RP2D). Results: As of July 2021, 18 pts were enrolled, and the last cohort (9 mg/kg) is underway. Patients received a median of 6 weeks’ treatment (range 2 – 45). There were no dose-limiting toxicities, dose modifications, or SAEs related to ST101. The only adverse events (AEs) of note were G1-2 histaminergic infusion-related reactions (IRRs), largely pruritis and urticaria, managed with antihistamines, montelukast, and interruption/slowing of infusion. IRRs affected 100% pts on the 1st dose of ST101 at 4mg/kg. Montelukast was added to the antihistamine premedication regimen in the 6 mg/kg cohort, which attenuated IRRs. 66% of patients in the 6 mg/kg experienced an IRR on the first dose. The intensity and frequency of IRRs decreased with repeat dosing across all cohorts. No other AEs were consistently reported. PK was dose-proportionate, with continued exposure. There was no evidence of accumulation, and no anti-drug antibodies were detected. Tumor immunohistochemistry showed dose-proportionate staining for ST101 and a trend of decreased Ki67 staining (proliferation marker) after ST101 exposure. One confirmed partial response in a patient with metastatic cutaneous melanoma refractory to standard therapy is still on study, and 3 pts with varied histologies have had stable disease lasting 18-45 weeks (1 ongoing). Conclusions: ST101 demonstrated safety at all doses explored and evidence of efficacy across dose levels, particularly higher doses. PK and PD support a dose relationship for efficacy, and we will select a QW RP2D for the phase 2 expansion cohorts by September 2021. Citation Format: Nehal J. Lakhani, Hendrik-Tobias Arkenau, Stefan N. Symeonides, Jeffry Evans, Meredith A. McKean, Elisa Fontana, Manojkumar Bupath, Alistair McLaren, Sreenivasa Chandana, Tze-en Ding, Emerson A. Lim, Jim Rotolo, Gina Capiaux, Rob Michel, Stephen Kaesshaefer, Alice S. Bexon, Gerald S. Falchook. ST101, a peptide targeting oncogenic transcription factor C/EBPβ: initial safety, efficacy, pharmacokinetic (PK) and pharmacodynamic (PD) data from an ongoing phase 1 dose escalation study in patients with advanced, metastatic solid tumors [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2021 Oct 7-10. Philadelphia (PA): AACR; Mol Cancer Ther 2021;20(12 Suppl):Abstract nr P06-03.
3014 Background: The oncogenic transcription factor CCAAT/enhancer-binding protein β (C/EBPβ) promotes tumor survival and proliferation and inhibits differentiation. ST101 is a peptide antagonist of C/EBPβ, with anti-tumor activity in prostate cancer (PC), glioblastoma (GBM), breast cancer (BC), melanoma, and other pre-clinical models. Methods: This phase 1 study enrolled patients (pts) with refractory solid tumors with varying histologies. The primary objective was to evaluate safety/tolerability of ST101 and to determine the recommended phase 2 dose (RP2D). Secondary and exploratory objectives included pharmacokinetics (PK), preliminary efficacy (RECIST 1.1), and pharmacodynamic (PD) evaluation. The study used a 3+3 dose-escalation design, with once-weekly IV infusion dosing of ST101 at 0.5, 1, 2, 4, 6, 9 mg/kg or a flat dose of 500 mg. Results: Enrollment in phase 1 was completed in November 2021 with a total of 25 pts with multi-metastatic disease that were refractory to standard therapy. As of February 15, 2022, five pts remain on study with a median treatment duration of 27 weeks’ (16-77). There were no DLTs, dose modifications, or serious adverse events (SAEs) related to ST101. The only AEs of note were G1-2 histaminergic infusion-related reactions (IRRs), largely pruritis and urticaria, managed with antihistamines, montelukast, and interruption/slowing of infusion. IRRs affected 93% of pts on the first dose at ≥4mg/kg and led to prolongation of infusion time. Intensity and frequency of IRRs decrease with repeat dosing. No other AEs were consistently reported. There was no evidence of accumulation upon continued exposure of ST101 and no anti-drug antibodies. Tumor immunohistochemistry showed dose-proportionate staining for ST101 and decreased tumor proliferation in several pts represented by decreased Ki67 expression. Population PK analysis supported flat dosing in phase 2. Five pts continue on treatment with one confirmed partial response in a patient with cutaneous melanoma lasting >42 weeks and four pts with ongoing stable disease. Conclusions: ST101 demonstrated safety at all doses explored and evidence of efficacy across dose levels, particularly higher doses and in pts with melanoma. PK and PD support a dose relationship for efficacy and selection of 500 mg as the RP2D. Pts are now enrolling in phase 2 cohorts to assess response in cutaneous melanoma, GBM, castrate-resistant PC, and HR+ BC. Clinical trial information: NCT04478279. [Table: see text]
Background: CCAAT/Enhancer Binding Protein Beta (C/EBPβ) is a transcription factor that is active during embryofetal development but held in an inactive state in most mature cells. C/EBPβ is upregulated or overactivated in multiple cancers, where it inversely correlates with disease prognosis. In breast cancer, C/EBPβ drives the expression of factors that promote tumor survival, proliferation and inhibit differentiation. ST101 is a cell-penetrating all D amino acid peptide antagonist of C/EBPβ. ST101 exposure inhibits C/EBPβ target gene expression, leading to selective tumor cell death in multiple human cancer cell lines, including hormone receptor positive breast cancer (HR+ BC) and triple negative breast cancer (TNBC), 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 proteolytic degradation. Potent ST101 anti-tumor activity, demonstrated by dose-dependent inhibition of tumor growth in subcutaneous HR+ and orthotopic TNBC xenograft models in vivo, supported advancing ST101 into clinical development.Trial design: This phase 1-2 study uses a standard 3+3 design with dose doubling for the first 4 dose levels then 50% escalations thereafter. The recommended phase 2 dose will be used in 4 expansion cohorts in specific tumor types, including HR+ BC. Patients receive intravenous ST101 once weekly.Eligibility criteria: The dose-escalation phase is enrolling patients ≥18 years of age with advanced, unresectable metastatic solid tumors refractory to or intolerant of other therapeutic options. In expansion, patients with HR+ BC must have progressed after 1-3 prior hormone-based therapies. Previous treatment with CDK 4/6 inhibitor, mTOR inhibitor, or chemotherapy is allowed as monotherapy or in combination. Specific aims: 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, analysis of pharmacokinetics, assessment of several pharmacodynamic measures, and to assess preliminary efficacy. Statistical design: The recommended phase 2 dose will be used in a 15-30 patient HR+ BC expansion cohort, with a Simon 2-stage design, which requires one response to expand the cohort to 30 patients. Up to 120 patients are planned in a total of four expansion cohorts, which should be enrolling by Q3 2021.Accrual: We began recruitment in August 2020. Enrollment is ongoing, and by July 2021, 18 patients were recruited in five dose-escalation cohorts up to 6 mg/kg; a 6th cohort (9 mg/kg) is ongoing. Dose escalation should be complete by Sept 2021, and the phase 2 portion in the HR+ BC cohort will be underway (n=15-30). Please contact rob.michel@bexonclinical.com if you have a specific interest in this trial. Citation Format: Alice S Bexon, Hendrik-Tobias Arkenau, Jeff Evans, Gerald S Falchook, Stefan N Symeonides, Meredith A McKean, Elisa Fontana, Manojkumar Bupath, Alistair McLaren, Sreenivasa Chandana, Tze-en Ding, Emerson A Lim, Jim Rotolo, Gina Capiaux, Rob Michel, Stephen Kaesshaefer, Nehal J Lakhani. Phase 1 study of ST101, a first-in-class peptide antagonist of CCAAT/enhancer-binding protein β (C/EBPβ), in patients with advanced solid tumors, with a phase 2 expansion in patients with hormone receptor positive breast cancer (HR+ BC) [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr OT2-01-01.
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