Sommerhalder, David

TPS3678 Background: Advanced and metastatic colorectal cancer (CRC) remains an area of significant unmet clinical need, particularly for patients with MSS/MSI-L tumors. In recent years, there have been several advancements in the treatment of solid tumors with T cell engagers. Our ATLAS scRNA-seq based discovery platform identified LY6G6D as a highly-specific tumor-associated antigen in advanced and metastatic CRC. CBI-1214, a CD3 bispecific T cell engager targeting LY6G6D with potent in vitro and in vivo activity even at low LY6G6D expression levels of ~300 copies/cell ( Yigit B et al, AACR 2025 ), is being developed for the treatment of patients with advanced or metastatic MSS/MSI-L CRC. Methods: This ongoing, open-label FIH study (CBI-1214-001) is being conducted to evaluate the safety, tolerability, pharmacokinetics (PK), and anti-tumor activity of CBI-1214 and to determine the maximum tolerated dose (MTD) and/or optimal biological dose (OBD) in participants with advanced or metastatic MSS/MSI-L CRC who have exhausted at least one prior line of systemic treatment and do not qualify for available targeted treatment options for actionable genomic alterations. Additional eligibility criteria include: at least 18 years of age, measurable disease (as defined by RECIST v1.1), available archival tumor tissue sample or a fresh tumor sample, ECOG PS 0 or 1, as well as adequate hematologic and organ functions. Patients whose CRC tumor tissues have been identified as dMMR or MSI-H are excluded. The study is conducted in two parts: Part 1 dose escalation, which starts with Part 1a as accelerated dose escalation, followed by Part 1b escalation, which is based on a modified toxicity probability interval (mTPI-2) design, and Part 2, which is designed as a randomized dose optimization study to select the final recommended phase 2 dose (RP2D). For both parts of the study, the study intervention is administered as monotherapy, given as an intravenous (IV) infusion, in 21-day treatment cycles, with a step-up option. After an up-to-28-day screening period, eligible patients receive study medication and are followed for their entire treatment period plus a follow-up period of approximately 90 days. The study is open for recruitment in the United States (NCT07321106). Clinical trial information: NCT07321106 .

Abstract Background: Pyrimidine synthesis is a therapeutic vulnerability in cancer but inhibition results in toxicity to normal cells. Differential targeting of CTP synthase 1 (CTPS1), sparing the CTPS2 isoenzyme, is a therapeutic strategy in lymphoid cancers, supported by human genetic studies, that can potentially avoid toxicity; however, CTPS2 activity may compensate in epithelial tumours. Loss of CTPS2 protein expression characterises 25% of solid tumours and is predicted to expose a synthetic lethal vulnerability to CTPS1 inhibition. Dencatistat (STP938) is a first in class oral CTPS1 inhibitor showing >1,300-fold selectivity over CTPS2. In preclinical studies, CTPS2 expression was confirmed as a key modulator of response to CTPS1 inhibition, and dencatistat induced tumour regression in an in vivo model of CTPS2 negative ovarian cancer. Study design: The study comprises a standard 3+3 phase 1a dose escalation design, in which intra-patient dose escalation is encouraged, followed by a phase 1b safety expansion. The dose escalation study is recruiting participants with high grade advanced tumours who have exhausted standard of care therapy (excluding haematological cancers, salivary gland tumours and low grade tumours of any tissue). In addition, participants with high grade serous ovarian cancer whose tumours lack expression of CTPS2 (per central laboratory testing by immunohistochemistry) are eligible for backfill into cleared cohorts during dose escalation. The recommended phase 2 dose (RP2D) will be nominated based on safety, tolerability, target engagement and early signs of clinical efficacy. The phase 1b safety expansion study will recruit participants with CTPS2 negative ovarian, lung or endometrial cancer who will receive treatment at the RP2D. Standard inclusion criteria apply; patients with ECOG performance score >2 (>1 for phase 1a in France) or active/symptomatic CNS metastases are not eligible. The primary objectives of the study are to evaluate the safety and tolerability of single agent dencatistat and to determine the RP2D for further development. Secondary objectives comprise evaluation of pharmacokinetic properties and preliminary clinical activity. Exploratory endpoints include evaluation of target engagement, molecular features associated with response, and determination of drug metabolites. The study opened to enrolment in the UK, France and USA in September 2024 and is currently in dose escalation (NCT06297525). The phase 1b study is expected to commence mid-2026 and will include additional centres in Spain. Citation Format: Donna M. Graham, David Sommerhalder, Douglas Orr, Rowan Miller, Neeharika Makani, David O'Malley, Ira Winer, Philip A. Beer, Karen Smith, Maureen Higgins, John R. Hawse, Xiyin Wang, Saravut J. Weroha, Christophe Massard, Patricia Roxburgh. Lack of CTPS2 expression exposes synthetic lethal vulnerability to selective CTPS1 inhibition: A phase 1 dose escalation study of dencatistat (STP938) with safety expansion in biomarker selected cohorts [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(8_Suppl):Abstract nr CT075.

3083 Background: Cancer-Specific Plectin (CSP) is a novel pro-tumorigenic target that is selectively expressed on the surface of tumors, while absent from benign tissue. CSP is highly expressed in many solid cancers, particularly pancreatic (PC), cholangiocarcinoma (CCA), and ovarian (OC). ZB131 (Zielbio), is a humanized anti-CSP IgG1 monoclonal antibody that binds specifically to CSP on the surface of tumor cells, rapidly internalizes and modulates key proliferative and cytoskeletal remodeling signaling pathways to decrease cancer cell growth and increase the recruitment of anti-tumor immune infiltrates. Methods: The dose escalation (3+3 design) and expansion are enrolling adult patients (pts) with advanced treatment-refractory solid tumors. ZB131 was administered IV over 60 minutes (without premedication) weekly. The starting dose of ZB131 is 0.3 mg/kg followed by 1,3, 9, 15 and 30 mg/kg. Primary objectives are safety, tolerability, and maximum tolerated dose/determination of Phase 2 dose. Secondary objectives are preliminary efficacy (RECIST v1.1), Pharmacokinetic (PK) and pharmacodynamic parameters in blood and paired tumor biopsies. Results: As of 31 Jan 2023, 24 pts had enrolled (9 PC, 6 CCA, 4 OC, 5 other). The median age was 59.5 yr (range, 35 – 84) with a median of 4 prior lines of therapy. The median ZB131 treatment duration is 5.3 weeks (range, 1 – 33). No dose-limiting toxicities were observed up to the dose of 30 mg/kg which is currently enrolling. Treatment-related adverse events (TRAEs) were grade 1/ 2: nausea (n=6), fatigue (n=5), anemia (n=3), diarrhea (n=2), flulike symptoms (n=2), and vomiting (n=2). Mild flu-like symptoms and nausea/vomiting were observed during or following infusion at doses of 9 mg/kg and above. Except for one episode of Gr 3 neutropenia at the 30 mg/kg dose, no other drug-related grade 3/4 TRAE’s were reported. Five pts had stable disease range, 12 – 33 weeks (2 PC, 1 CCA, 2 OC), with a 43% decrease in CA-125 observed in one OC pt. The PKs are linear and dose-proportional for all dose levels evaluated (estimated T ½ of 6-9 days). No antidrug antibodies have been detected. Conclusions: Interim data from dose-escalation of this first-in-class, anti CSP antibody, demonstrates good tolerability with encouraging signs of activity and target engagement in heavily pretreated pts. Results support further clinical evaluation of ZB131 in dose-expansion cohorts including OC and including combination therapy with gemcitabine. Clinical trial information: NCT 05074472 .

Abstract Background: The dysregulation of polycomb repressive complex 2 (PRC2) promotes tumorigenesis and progression. Two therapeutic agents targeting enhancer of zeste homolog (EZH) 2 or EZH1/2, the catalytic subunits of PRC2, have been approved in several cancer types. HH2853 is a novel selective EZH1/2 dual inhibitor, which has demonstrated superior anti-tumor efficacy to tazemetostat (EZH2 inhibitor approved by FDA) in various preclinical models. Methods: This is a first-in-human, open-label, multi-center, phase (Ph) I/II study of HH2853 in patients (pts) with relapsed/refractory (r/r) non-Hodgkin lymphomas (NHLs) or advanced solid tumors. HH2853 was administered orally twice daily (BID) on a continuous 28-day treatment cycle. Ph I consist of two parts: dose escalation part adopting accelerated titration followed by a Bayesian optimal interval design and dose extension part. Dose limiting toxicity (DLT) was evaluated during the 1st cycle in dose escalation. Safety, tolerability, pharmacokinetics (PK), pharmacodynamics (PD) and preliminary anti-tumor activity of HH2853 were explored in this Ph I study. Results: As of Oct 19, 2022, a total of 57 pts, including 50 pts with solid tumors and 7 pts with r/r follicular lymphoma (FL), were enrolled from 12 sites in China and the US. Twenty-five (43.9%) pts received ≥3 lines of prior systemic therapies. Six dose levels(50 mg, 100 mg, 200 mg, 400 mg, 600 mg and 800 mg)were evaluated. DLTs were observed in 2 of 8 DLT evaluable pts at 800 mg: one grade 3 platelet count decreased and one grade 3 diarrhea. A conclusive maximal tolerated dose was not reached. The most common treatment-related adverse events (TRAE) were diarrhea (45.6%), blood bilirubin increased (35.1%), white blood cell count (WBC) decreased (26.3%), platelet count decreased (26.3%), rash (24.6%) and anemia (22.8%). The most common ≥grade 3 TRAEs included anemia (8.8%), platelet count decreased (7.0%), WBC decreased (5.3%) and diarrhea (5.3%). TRAEs leading to dose interruption or reduction were reported in 17.5% and 8.8% pts respectively. No TRAE led to dose discontinuation or death. PK data indicated dose-related increase in exposure from 50 to 600 mg. PD data showed a significant inhibition (maximum reached >90%) of H3K27me3 in granulocytes and monocytes at 400-800 mg. Tumor responses were observed in 7 pts from 200 to 800 mg in multiple tumor types, including complete response in 1 patient with FL, partial response in 3 pts with epithelioid sarcoma, 2 pts with FL and 1 patient with malignant rhabdoid tumor of pancreas. Conclusions: This first-in-human study of HH2853 showed a manageable safety profile and promising anti-tumor activity in multiple tumor types, supporting further exploration in NHLs and solid tumors after recommended Ph II dose is determined.Clinical trial information: NCT04390737 Citation Format: Zhengfu Fan, Jin Wang, Meiyu Fang, Johnston Patrick, Tun Han, David Sommerhalder, Jifang Gong, Jilong Yang, Yun Yang, Javier Munoz, Yuqin Song, Zhiming Li, Xian'an Li, Qiuying Ma, Jinming Han, Lin Shen, Jun Zhu. Preliminary results from the Phase I part of a first-in-human Phase I/II study of HH2853, an EZH1/2 inhibitor, in patients with relapsed/refractory non-Hodgkin lymphomas or 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 CT105.