e24005 Background: E7386 is a novel oral anticancer agent that inhibits the interaction between β-catenin and CREB-binding protein. Phase 1 studies provide an efficient approach to cardiac safety assessment by using data across a range of doses to model the concentration-QTc (C-QTc) relationship; such modeling enables early detection of cardiac risk. The analysis described herein was conducted to evaluate cardiac safety and assess the potential effect of E7386 on ECG parameters, including the QTcF interval. Methods: C-QTc analyses were performed using E7386 plasma concentrations and continuous Holter ECG data collected on C1D1 and C1D8 (at steady state) from two phase 1 monotherapy studies in patients (pts) with solid tumors: Study 101 (NCT03264664; data available from 25 pts treated with E7386 at doses ranging from 10-120 mg twice daily [BID]) and Study 103 (NCT03833700; data available from 18 pts treated at the E7386 monotherapy RP2D of 120 mg BID). The relationship between E7386 plasma concentrations and change-from-baseline QTcF (ΔQTcF) was investigated using a linear mixed-effects modeling approach. The concentration level at which the upper bound of the 2-sided 90% CI of model-predicted ΔQTcF exceeded 10 ms was determined. Results: E7386 showed no clinically significant impact on cardiac conduction parameters (PR and QRS intervals) or heart rate across the studied dose ranges. Observed changes on heart rate were minimal and unlikely to influence the C-QTc analysis. The absolute slopes of QTcF vs RR were minimal, indicating negligible effect on the C-QTc assessment. Consequently, additional heart rate correction methods were not warranted. Hysteresis was not present. Neither the fixed intercept nor the slope for the E7386 ─ C-QTc relationship were statistically significant. C-QTc analysis showed no clinically meaningful QTc effect (ΔQTcF >10 ms) for E7386 concentrations up to 2650 ng/mL in Study 103. Consistent results were seen in Study 101 with exclusion of a QTc effect up to E7386 concentrations of 2300 ng/mL. Results from the C-QTc analyses in Study 103 and 101 indicate substantial cardiac safety margins of ~5.70 and ~3.36‐fold, respectively, over corresponding clinical C max,ss values reported for the E7386 RP2D of 120 mg BID (Study 103, 464.8 ng/mL; Study 101, 684.0 ng/mL). Conclusions: Phase 1 C-QTc evaluations of E7386 offer critical insights on cardiac safety that inform dose selection and monitoring strategies for further clinical development. The predicted mean ΔQTcF and its 90% CI upper bound remained below 10 ms for concentrations up to 2650 ng/mL, based on C-QTc analysis of two phase 1 studies. No significant cardiac safety concerns were identified at the studied dose levels. Clinical trial information: NCT03264664 , NCT03833700 .

TPS2681 Background: The immunosuppressive pathway of prostaglandin E 2 (PGE 2 ), part of the cyclooxygenase (COX) pathway, is upregulated in certain cancers and has been implicated in tumor evasion of CD8 T, NK, and dendritic immune cells, allowing tumor growth and metastasis (Jin et al., 2023). COX2 inhibitors, aspirin and nonsteroidal anti-inflammatories (NSAIDS) have shown some survival benefit in patients with gastrointestinal cancer and others (Cao et al., 2016; Martling et al., 2025; Takiuchi et al., 2018; Zhang et al., 2025); however, results are inconsistent, likely due to toxicity limiting complete blockade of the pathway, highlighting the need for more potent but selective inhibitors. OKN4395 is a first-in-class, highly selective, equipotent inhibitor of EP2, EP4, and DP1, downstream receptors for COX-derived PGE 2 , and PGD 2 , respectively. DP1 has described roles in immunosuppression and inhibition of apoptosis, supporting the therapeutic rationale (Luo et al., 2024; Peinhaupt et al., 2017). OKN4395 is hypothesized to modulate the tumor microenvironment to allow an effective immune response as monotherapy, and to potentiate the effect of immunotherapies such as checkpoint inhibitors, both of which are evaluated in INVOKE. Tumor types for INVOKE were selected using previously presented multimodal artificial intelligence (AI) drug-matching algorithms (Grimaldi, et al., 2025). Methods: INVOKE (OKN-4395-121; NCT06789172) is a Ph1a/1b, first-in-human study of OKN4395 (oral, BID) as monotherapy (mono) or in combination with a PD1 checkpoint inhibitor (combo), in patients with advanced solid tumors. Ph1a is a Bayesian dose escalation in mono with a new parallel substudy, followed by combo dose confirmation, primarily assessing safety, establishing the Ph1b dose. Response will be assessed in updated Ph1b (cohorts of n=20): select sarcomas (mono), non-small cell lung (combo), colorectal (combo), and gastric cancer (combo). Key inclusion criteria include COX-active (Ph1a) or above-listed (Ph1b) tumors, performance status 0-1, biopsy-amenable lesions, and adequate organ function. Active CNS metastases, upper GI bleed risk factors, untreated H. pylori infection, and concomitant NSAIDs/COX inhibitors/prostaglandins are exclusionary. A new and innovative 3-period, crossover substudy in parallel with Ph1a will explore the intra-participant effects of food and gastric pH on OKN4395 pharmacokinetics. Trial data, paired pre- and on-treatment biopsies, and exploratory biomarkers will be used to enhance development using advanced agentic AI systems, including a synthetic digital twin control arm, novel methodology of which is submitted to this meeting as well. Ph1a of the study is currently recruiting in the US, UK, and Australia. Dose Level 5 concluded in December 2025 with no DLTs to that date. Clinical trial information: NCT06789172 .

The hedgehog (Hh) signalling pathway is aberrantly activated in solid tumours. Inhibition of Hh signalling by SMO inhibitors is effective in the treatment of basal cell carcinomas and medulloblastomas whereas combination treatments may be required in other solid tumours. When given with an SMO inhibitor in preclinical models, the efficacy of paclitaxel is enhanced and there is potential reversal of mechanisms of resistance to paclitaxel supporting clinical investigation of the combination. In this phase I trial, the safety and feasibility of the oral SMO inhibitor, taladegib, was evaluated in combination with weekly paclitaxel in patients with advanced solid tumours. This was an open-label, nonrandomised, multicentre, dose escalation trial using a standard 3 + 3 design (EudraCT: 2014-004695-37 ISRCTN15903698). Primary objectives were to determine dose-limiting toxicities and the maximum tolerated dose of the combination. Patients received up to 6 cycles of paclitaxel 80 mg/m2 (day 1, 8 and 15 of a 28-day cycle). Then, 16 patients were recruited into 3 cohorts and received taladegib at 100 mg, 200 mg and 400 mg once daily, respectively. Grade 2/3 peripheral sensory neuropathy was the dose-limiting toxicity. The maximum tolerated dose of taladegib in combination with weekly paclitaxel was 200 mg once daily. Four patients had a partial response and 4 had confirmed stable disease at 16 weeks. The combination is feasible but cumulative neuropathy may limit longer term treatment. Hh signalling may be implicated in chemotherapy-induced neuropathy.

TPS793 Background: mPDAC has a poor prognosis with a median overall survival < 1 year with chemotherapy. Gremlin-1, secreted by cancer-associated fibroblasts and tumor cells, represses bone morphogenetic protein (BMP) signalling, thereby promoting proliferation and invasiveness. GREM1 mRNA is detected in the stroma of approximately 70% of PDAC cases. Gremlin-1 protein expression correlates with poor prognosis in PDAC. In pre-clinical models, Ab7326 (murine version of ginisortamab), blocks gremlin-1 BMP binding, restores BMP-2, 4, & 7 signalling and downstream SMAD pathway activation, and increases survival in the gremlin-1 expressing KPC murine model of PDAC in combination with either gemcitabine or MEK inhibition. Ginisortamab, a fully humanised IgG monoclonal antibody, was well tolerated when administered as monotherapy by intravenous (IV) infusion on days 1 & 15 of a 28-day cycle in pts with advanced refractory cancers in a first-in-human ONCO01 study (https://clinicaltrials.gov/study/NCT04393298). Methods: Phase II multi-centre study (UK, Norway, Spain, Germany) with safety run-in and dose expansion (proof of concept) in 2 modules in pts with mPDAC, ECOG ≤ 1, adequate organ function, RECIST1.1 measurable disease. Module 1 (no prior chemotherapy for mPDAC): non-randomised exploratory efficacy study (n = 60) with primary outcomes of progression-free survival (PFS) and disease control rate (DCR) at 16 weeks. Pts receive ginisortamab 2000mg IV infusion on days 1 & 15 with AG (standard doses) IV on days 1, 8, 15 (28-day cycle). Radiological assessment (RECIST1.1), QoL, CA19-9 every 8 weeks. PK collected days 1, 2, 4, 8, 15, 16, 18, 22 (cycle 1), days 1, 8, 15 (cycle 2) and pre-infusion days 1, 15 other cycles (safety run-in pts). Mandatory pre- and on-treatment (cycle 2 day 8 +/- 5 days) tumor biopsy to include SMAD4 and gremlin-1 expression (all pts). Module 1 commenced recruitment Q2 2024. Module 2: mPDAC (n = 60) with ongoing stable disease or response after ≥ 16 weeks of standard of care 1 st -line chemotherapy, randomised 2:1 to ginisortamab (IV days 1, 15) + MEK inhibitor vs observation with primary outcome of PFS. Module 2 is planned to commence in Q3 / Q4 2025. This study is funded and sponsored by Cancer Research UK in collaboration with UCB. The EU CT Number is 2024-514129-43, and the IRAS Identifier is 1007925. Clinical trial information: NCT04393298 .

705 Background: The tumor microenvironment encompasses complex interactions between cancer cells, fibroblasts, and immune cells, including induction of matricellular proteins that can promote tumorigenesis. One such factor is the bone morphogenetic protein (BMP) antagonist gremlin-1, which has been linked to poor prognosis in multiple human cancer types, including pancreatic ductal adenocarcinoma (PDAC), which has a poor 5-year survival and high unmet clinical need. Ginisortamab (a fully human gremlin-1 monoclonal antibody) and its murine analog Ab7326 (mouse immunoglobulin G1) block gremlin-1’s interaction with BMPs 2, 4, & 7, thereby promoting BMP signaling. Methods: We used a genetically engineered mouse model of pancreatic cancer to evaluate the therapeutic effect of antibody-mediated inhibition of gremlin-1 (Ab7326) alone, or in combination with gemcitabine or a MEK 1/2 inhibitor (selumetinib or UCB-554). LSL-Kras G12D/+ ; LSL-Trp53 R172H/+ ; Pdx1-Cre (KPC) mice develop spontaneous tumors that mimic human pancreatic cancer in aggression, metastatic potential, and chemotherapy resistance. Treatment of mice was initiated once the cancer was detected by ultrasound imaging, and tumor growth was measured weekly by high-resolution ultrasound until humane endpoints. The Log-rank Mantel-Cox test was used to compare survival times between treatment groups. Results: Treatment with Ab7326 (30 mg/kg subcutaneous injection [s.c.], twice weekly) or gemcitabine (100 mg/kg intraperitoneal injection, twice weekly) alone had a modest effect on survival in this model; however, mice treated with the combination of the two showed a significant increase in survival (n=6, median 36.5 days [range 20–93], p=0.037) compared with vehicle controls (n=6, median 20 days [range 3–29]). Similarly, treatment with a MEK inhibitor alone had a limited effect on survival, but combination of Ab7326 (30 mg/kg s.c. twice weekly) with either selumetinib (25 mg/kg orally, twice daily), or UCB-554 (10 mg/kg orally, every 2 days), slowed tumor growth and significantly prolonged survival (Ab7326 + selumetinib [n=10]: median 29.5 days [range 12–89], p=0.022; Ab7326 + UCB-554 [n=11]: median 32 days [range 16–61], p=0.003) over vehicle controls (n=10, median 12 days [range 7–56]). Conclusions: Blocking gremlin-1 in combination with gemcitabine or MEK inhibition may have benefit in the treatment of pancreatic cancer. Ginisortamab is now in a Phase 2 clinical trial in patients with PDAC.

BACKGROUND:We present data from the Phase 1 open-label Study 101 of E7386, an oral protein-protein interaction inhibitor reported to block the CBP/β-catenin interaction, in patients with solid tumours. METHODS:Eligible patients (across the UK and US) aged ≥18 years had advanced/recurrent solid tumours (dose-escalation) or CTNNB1-mutated hepatocellular carcinoma (dose-expansion). Primary objectives were to assess safety/tolerability and determine the recommended Phase 2 dose (RP2D) of E7386. RESULTS:Thirty-eight patients received study drug (dose-escalation: n = 32; expansion: n = 6; dose-range: 5-120 mg twice daily [BID]); 60.5% received ≥3 prior anticancer medications. Dose-limiting toxicities (grade-2 lethargy and grade-2 decreased appetite) occurred in 1 patient (20 mg BID cohort). The RP2D was determined as 120 mg BID. Most (94.7%) patients experienced treatment-related adverse events (TRAEs), most frequently nausea (65.8%) and vomiting (60.5%), which were primarily grade 1/2 and well-managed with antiemetics. No grade 4/5 TRAEs were noted. Pharmacokinetic exposure increased with increasing dose, although large intersubject variability was observed. No objective responses were noted; stable disease (SD) was observed in 36.8% of patients, including SD ≥ 23 weeks in 18.8% of patients (dose-escalation). CONCLUSIONS:E7386 demonstrated a manageable safety profile, a dose-dependent pharmacokinetic profile, and some disease stabilisation in heavily pretreated patients with advanced solid tumours. TRIAL REGISTRATION:NCT03264664 https://clinicaltrials.gov/study/NCT03264664 .

e15113 Background: Faridoxorubicin (faridox, AVA6000) is a cleavable peptide drug conjugate (PDC) comprised of doxorubicin (dox) bound to a peptide by a linker that is specifically cleaved by FAP, which is overexpressed in the tumor microenvironment (TME) of many solid tumors. This PDC technology utilizes a mask and release technology to concentrate released payload in the TME. Methods: The safety, pharmacokinetics (PK) and preliminary efficacy of faridox were established in a first-in-human, multicenter Phase 1a and 1b trial with faridox administered i.v. q3w or q2w using a 3+3 design in patients with locally advanced or metastatic solid tumors. The Phase 1b expansion portion enrolled patients with salivary gland cancer (SGC), soft tissue sarcoma (STS) and triple negative breast cancer (TNBC) patients at the Phase 1a RP2D of 310 mg/m 2 Q3W. AUC based dosing was initially utilized to calculate maximum safe number of cycles of AVA6000, equivalent to a cumulative dox dose of 550 mg/m 2 ; this lifetime limit was lifted during Phase 1b based on absence of cardiac toxicity. Results: Results of the faridox Phase 1a escalation in 63 patients were previously reported (Lahu et al, ESMO 2025). In the Phase Ib expansion portion, an additional 27 patients with SGC, TNBC or STS have been dosed as of the data cutoff (median age 62 yr, range 32-81; 44% male; 63% ECOG 0). The safety profile in Phase Ib was favorable and consistent with Ph Ia observations; the most frequent AEs being fatigue (56%), alopecia (52%), nausea (44%), anemia (26%), and neutropenia (22%). Grade 3-4 hematologic toxicities included neutropenia (11%) and lymphopenia (4%). No grade 3 or 4 cardiac events or clinically relevant changes in left ventricular ejection fraction were observed despite faridoxorubicin being dosed to dox exposures associated with a cumulative dose of 550 mg/m 2 . Based on the favorable cardiac safety data, the lifetime maximum dox exposure was lifted during the trial. Compared to conventional dox, PK showed reduced systemic exposure (AUC, up to 77% reduction), reduced volume of distribution and higher tumor concentrations (median 117:1 ratio of tumor to plasma exposure of released dox). In the 30 patients with SGC treated across Phase 1a and 1b (n = 11 and 19), 2 pts with partial responses and 25 pts with stable disease were observed for a disease control rate of 90%. Median PFS in the SGC cohort has not been reached with median follow up exceeding 5 mos in the combined cohort (9 mos in Ph Ia). Efficient dox production was observed in the TME with FAP IHC levels ranging from 1+-3+ by immunohistochemistry in SGC. Conclusions: Faridox is active in SGC and well tolerated, delivering high concentration of free dox to the TME relative to plasma. Responses were observed and prolonged disease stabilization in patients with SGC indicating activity of the PDC. Clinical trial information: NCT04969835 .

Transparent and accurate reporting in early phase dose-finding (EPDF) clinical trials is crucial for informing subsequent larger trials. The SPIRIT statement, designed for trial protocol content, does not adequately cover the distinctive features of EPDF trials. Recent findings indicate that the protocol contents in past EPDF trials frequently lacked completeness and clarity. To address this gap, the international consensus-driven SPIRIT-DEFINE checklist was developed through a robust methodological framework for guideline development, with the aim to improve completeness and clarity in EPDF trial protocols. The checklist builds on the SPIRIT statement, adding 17 new items and modifying 15 existing ones.The SPIRIT-DEFINE explanation and elaboration (E&E) document provides comprehensive information to enhance understanding and usability of the SPIRIT-DEFINE checklist when writing an EPDF trial protocol. Each new or modified checklist item is accompanied by a detailed description, its rationale with supportive evidence, and examples of good reporting curated from EPDF trial protocols covering a range of therapeutic areas and interventions. We recommend utilising this paper alongside the SPIRIT statement, and any relevant extensions, to enhance the development and review of EPDF trial protocols.By facilitating adoption of the SPIRIT-DEFINE statement for EPDF trials, this E&E document can promote enhancement of methodological rigour, patient safety, transparency, and facilitate the generation of high-quality, reproducible evidence that will strengthen the foundation of early phase research and ultimately improve patient outcomes. Funding This work is a further extension of the SPIRIT-DEFINE study, which obtained no external funding. The principal investigator (CY) used internal staff resources, together with additional resources from external partners, to conduct this study. The SPIRIT-DEFINE study is a component of the DEFINE project, which also developed the MRC/NIHR funded CONSORT-DEFINE guidance. ICR-CTSU receives programmatic infrastructure funding from Cancer Research UK (C1491/A25351; CTUQQR-Dec22/100004), which has contributed to accelerating the advancement and successful completion of this work.

TPS2683 Background: Immunotherapy is an established cancer therapy, although mechanisms of non-response & resistance are emerging, leaving few options post-relapse. The immunosuppressive pathway of prostaglandin E 2 (PGE 2 ), part of the cyclooxygenase (COX) pathway, is upregulated in certain cancers and has been implicated in tumor evasion of CD8 T, NK, and dendritic immune cells, allowing tumor growth and metastasis (Jin et al., 2023). COX2 inhibitors, aspirin and nonsteroidal anti-inflammatories (NSAIDS) have shown some survival benefit in patients with colon, lung, prostate, and endometrial cancer (Cao et al., 2016; Lim et al., 2012; Huang et al., 2014; Takiuchi et al., 2018), however results are inconsistent, likely due to toxicity limiting complete blockade of the pathway, highlighting the need for more potent but selective COX pathway inhibitors. OKN4395 is a first-in-class, highly selective, equipotent inhibitor of EP2, EP4 and DP1, downstream receptors for COX-derived PGE 2 , and PGD 2 , respectively. DP1 has described roles in immunosuppression and inhibition of apoptosis, supporting the therapeutic rationale (Luo et al., 2024; Peinhaupt et al., 2017). OKN4395 is hypothesized to modulate the tumor microenvironment to allow an effective immune response as monotherapy, and to potentiate the effect of immunotherapies such as checkpoint inhibitors, both of which are evaluated in INVOKE. Methods: INVOKE (OKN-4395-121; NCT06789172) is a Ph1a/1b, first-in-human study of OKN4395 (oral, BID) as monotherapy (mono) or in combination with pembrolizumab 200mg IV 3-weekly (combo), in patients with advanced solid tumors that have evidence of COX-associated immunosuppression. Ph1a is a Bayesian dose escalation in mono, followed by combo dose confirmation, primarily assessing safety, establishing the optimal dose for Ph1b. Using multimodal artificial intelligence (AI) drug-matching algorithms, Ph1b tumor types were selected, and response will be assessed (cohorts of n = 20 each): select sarcomas (mono), pancreatic carcinoma (mono), non-small cell lung cancer (combo), colorectal carcinoma (combo), head and neck squamous cell carcinoma (combo). Key inclusion criteria include COX-active (Ph1a) or above-listed (Ph1b) tumors, performance status 0-1, biopsy-amenable lesions, and adequate organ function. Active CNS metastases, upper GI bleed risk factors, untreated H. pylori infection, and concomitant NSAIDs/COX inhibitors/prostaglandins are exclusionary. Ph1b mono cohorts will include exploratory analyses including evaluation of the effect of food & gastric pH on OKN4395 pharmacokinetics. Trial data, paired pre- and on-treatment biopsies, and exploratory biomarkers will be used to enhance development using advanced agentic AI systems, including a synthetic digital twin control arm. Ph1a of the study is currently recruiting in the US, UK, and Australia. Clinical trial information: 06789172 .

Combination chemotherapy provides significant survival advantage in patients with advanced gastro-oesophageal adenocarcinoma compared with best supportive care. Peri-operative chemotherapy is standard of care for patients with operable disease. We hypothesised that biomarkers of genomic instability and inflammation may have clinical utility in these patients. We initiated open-label, non-randomised biomarker studies in patients with advanced disease due to receive Epirubicin, Cisplatin and Capecitabine (ECX)/Epirubicin, Cisplatin and Fluorouracil (ECF) or Epirubicin, Oxaliplatin and Capecitabine (EOX)/Epirubicin, Oxaliplatin and Fluorouracil (EOF) regimens (advanced study, n = 375), and in patients planned to receive perioperative chemotherapy with the same regimen (peri-operative study, n = 306). Relative telomere length (RTL) in peripheral blood mononuclear cells (PBMCs) and plasma levels of 10 inflammatory cytokines were analysed to determine association with progression-free and overall survival, and response. Blood samples were collected prior to treatment and on each treatment cycle. Both studies comprised biomarker discovery and validation cohorts. Here we report analysis of the discovery cohorts. In advanced disease, high pre-treatment levels of IL8 and IL10 associated with poor Progression Free Survival (PFS) and Overall Survival (OS) in univariate analysis, and IL6 with poor OS. In multivariate analysis, IL6 and IL8 remained associated with OS, and IL8 with PFS. In the perioperative study, cytokine levels were significantly lower and no relationships were observed. There was no association between RTL and any endpoint in either study. Pre-treatment RTL was not prognostic, although IL6/IL8 were negative prognostic factors in advanced disease. Levels of these were lower in patients with localised disease, suggesting an association with disease progression. Further analysis of systemic inflammatory status in gastro-oesophageal adenocarcinoma may be promising for development of future predictive biomarker signatures.

Early phase dose-finding (EPDF) trials are key in the development of novel therapies, with their findings directly informing subsequent clinical development phases and providing valuable insights for reverse translation. Comprehensive and transparent reporting of these studies is critical for their accurate and critical interpretation, which may improve and expedite therapeutic development. However, quality of reporting of design characteristics and results from EPDF trials is often variable and incomplete. The international consensus-based CONSORT-DEFINE (Consolidated Standards for Reporting Trials Dose-finding Extension) statement, an extension of the CONSORT statement for randomised trials, was developed to improve the reporting of EPDF trials. The CONSORT-DEFINE statement introduced 21 new items and modified 19 existing CONSORT items.This CONSORT-DEFINE Explanation and Elaboration (E&E) document provides important information to enhance understanding and facilitate the implementation of the CONSORT-DEFINE checklist. For each new or modified checklist item, we provide a detailed description and its rationale with supporting evidence, and present examples from EPDF trial reports published in peer-reviewed scientific journals. When reporting the results of EPDF trials, authors are encouraged to consult the CONSORT-DEFINE E&E document, together with the CONSORT and CONSORT-DEFINE statement papers, and adhere to their recommendations. Widespread adoption of the CONSORT-DEFINE statement is likely to enhance the reporting quality of EPDF trials, thus facilitating the peer review of such studies and their appraisal by researchers, regulators, ethics committee members, and funders. Funding:This work is a further extension of the CONSORT-DEFINE study, which was funded by the UK Medical Research Council (MRC)-National Institute for Health and Care Research (NIHR) Methodology Research Programme (MR/T044934/1). The Clinical Trials and Statistics Unit at The Institute of Cancer Research (ICR-CTSU) receives programmatic infrastructure funding from Cancer Research UK (C1491/A25351; CTUQQR-Dec 22/100 004), which has contributed to accelerating the advancement and successful completion of this work.

Abstract Introduction Pancreatic Cancer (PC) remains almost universally lethal. Precision-Panc UK therapeutic development platform was established to overcome challenges of delivering precision medicine and accelerate drug development for PC. Methods A Master Protocol (MP) was established to screen, biopsy, and molecularly profile patients for subsequent enrolment into multiple PRIMUS clinical trials. Research patient and tissue pathways were incorporated into routine clinical practice for molecular profiling using a bespoke Clinical Cancer Genome assay utilising targeted capture next generation sequencing technology. Whole transcriptome is performed using BioClavis Temp-O-Seq technology. In addition, tumor NGS of selected cases are discussed in the virtual Precision-Panc Molecular Tumor Board for collective interpretation of results, and to support of clinical decision making, trial enrolment and precision medicine. Results (updated data to be presented if selected for presentation) To date, 670 patients have been screened for Precision-Panc, 567 patients were registered on the MP, and 336 enrolled in PRIMUS trials. Main reasons for attrition were decline in performance status, death, alternative diagnosis, or patient declined active treatment or PRIMUS trials. Tissue biopsies were obtained either by endoscopic ultrasound or interventional radiology as part of diagnostic pathway. Sixty five of the 483 samples submitted to the sequencing laboratory contained insufficient material (13% upstream sample fail). Of the 418 samples sequenced, a clinical grade report could be issued for 393 (94%) samples (6% failed sequencing/analysis QC matrix). Most patients carried KRAS G12D mutations (48%), followed by G12V (30%), G12R (12%), Q61H (6%) and G12C (1%), leading to different downstream signalling on transcriptomic pathway analysis. KRAS wildtype was seen in 35 cases (8.9%). Homologous recombination deficiency genomic scar was seen in ~10% (biomarker for the PRIMUS-001 and -002 trials, evaluating FOLFOX-A versus AG as first-line treatment for metastatic PC or in the neoadjuvant setting). Somatic driver variants in RNF43 were detected in 25 patients (7%) (PRIMUS-007, 2nd line trial of porcupine inhibitor RXC004 in RNF43 mutated advanced PC). Four patients (1.2%) were found to be MSI high and 32 (9.3%) had a TMB≥4mutations/Mb (eligible for PRIMUS-008; Pembrolizumab/Olaparib in patients with high TMB). Transcriptomic profiling confirmed previously described molecular subtypes with a relatively higher percentage of squamous/basal-like cancers in patients who rapidly deteriorated and dropped off the treatment pathway. Conclusion We present the initial experience and real-world challenges in longitudinal fashion in delivering precision medicine for PC, with attrition in both patient and tissue pathways. The majority of samples were successfully sequenced, and research activities were embedded in routine clinical practice, enabling easier trial enrolment, therapeutic and biomarker development for PC. Citation Format: Fieke E.M. Froeling, Juan Valle, Rosie Upstill-Goddard, Paul Grimwood, Paul Westwood, Stephan B. Dreyer, Caroline Kelly, Fraser Duthie, Judith Dixon, Sarah Bradley, T.R. Jeffry Evans, Owen J. Sansom, Andrew V. Biankin, David K. Chang. Therapeutic development platform for pancreatic cancer in the UK national health service: Lessons learned and initial results from Precision-Panc [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Pancreatic Cancer; 2023 Sep 27-30; Boston, Massachusetts. Philadelphia (PA): AACR; Cancer Res 2024;84(2 Suppl):Abstract nr PR04.

4094 Background: In REFLECT, LEN had superior ORR and PFS versus SOR in pts with uHCC ( P<0.0001); OS was noninferior. In this post-hoc analysis, we determined baseline mutation (MUT) status by plasma ctDNA and analyzed its association with clinical outcomes. Methods: In REFLECT, pts with untreated uHCC received either LEN 8 or 12 mg daily or SOR 400 mg twice daily. Tumor responses were measured per mRECIST by independent review. Baseline MUT status in ctDNA was measured by a PGDx elio Plasma Complete panel. We explored associations between ctDNA MUT status and ORR via Fisher's exact test or PFS/OS via Cox regression/log rank test. Results: 167 Pts enrolled to LEN and 86 pts enrolled to SOR had evaluable baseline ctDNA. The ctDNA population had a lower % of Asian pts (27% vs 67%) and pts with HBV etiology (27% vs 53%), and a higher % of Western pts (73% vs 33%) and pts with alcohol etiology (14% vs 6%) than the intention to treat (ITT) population. In the ctDNA population, a lower % of pts treated with LEN versus SOR had an AFP of <200 ng/mL (57% vs 70%) and HCV etiology (27% vs 44%); a higher % with LEN versus SOR had HBV etiology (32% vs 17%). In SOR-treated pts, slight differences in the median (m) PFS/mOS were observed between the ITT and ctDNA populations (Table). Among the ctDNA population (n=253), the most frequent MUT genes were TERT(48%), TP53(38%), and CTNNB1(27%). TERT/ CTNNB1MUT rates were higher in SOR-treated pts (56%/40%) than in LEN-treated pts (44%/20%). Gene MUT status was generally not associated with ORR in either arm. Similarly, MUT status was not associated with PFS with LEN; with SOR, pts with TP53 and TERT MUT showed shorter trends in PFS. OS with LEN was shorter in pts with TP53 MUT than WT; OS with SOR was shorter in pts with TERT, TP53,and CTNNB1 MUT. Results of LEN versus SOR by MUT subgroups will be presented. Conclusions: TERT, TP53, and CTNNB1 MUT had little effect on tumor response in either treatment arm; TP53 MUT appeared to be a factor for poor OS prognosis in both arms. Further analysis is needed due to the differences in baseline characteristics between ctDNA and ITT pts, and the difference in sample size between arms. Clinical trial information: NCT01761266 . [Table: see text]

Purpose:To evaluate safety, preliminary efficacy, pharmacokinetics, and pharmacodynamics, of fostroxacitabine bralpamide (fostrox, MIV-818), a novel oral troxacitabine nucleotide prodrug designed to direct exposure to the liver, while minimizing systemic toxicity. Patients and Methods:Fostrox monotherapy was administered in an open-label, single-arm, first-in-human, phase 1a/1b study, in patients with hepatocellular carcinoma (HCC), intrahepatic cholangiocarcinoma, or solid tumor liver metastases. The first part (1a) consisted of intra/inter-patient escalating doses (3 mg to 70 mg) QD for up to 5 days, and the second part (1b), doses of 40 mg QD for 5 days, in 21-day cycles. Safety and tolerability were evaluated by the Safety Review Committee, and efficacy was assessed every 6 weeks with CT or MRI using RECIST 1.1 and mRECIST. Results:Nineteen patients were treated with fostrox. Most common adverse events (AEs) were hematological and increased AST. Grade 3 treatment related AEs (TRAE) were seen in 53% of the patients, with transient neutropenia and thrombocytopenia as the most common. No grade 5 AE was observed. Recommended Phase 2 dose of fostrox was 40 mg QD for 5 days in 21-day cycles. Preliminary efficacy showed a clinical benefit rate in the liver of 53% and stable disease (SD) as best response in 10 patients. Liver targeting with fostrox was confirmed with higher exposure of troxacitabine and its metabolites in liver compared to plasma. Systemic exposure of fostrox was generally low with troxacitabine as main analyte. Biopsies demonstrated tumor-selective, drug-induced DNA damage. Conclusion:The phase 1a/1b monotherapy study of fostrox, in patients with liver tumors, showed a tumor selective effect in the liver and that 40 mg QD for 5 days in 21-day cycles is safe and tolerable. Safety and preliminary efficacy in patients with advanced HCC supports clinical development of fostrox in combination with other modes of action in HCC.

TPS3170 Background: CV6-168 is a FIC DNA uracilation agent targeting the enzyme dUTPase with high specificity. CV6-168 induces misincorporation of uracil into DNA when combined with thymidylate synthase (TS) inhibitors resulting in significantly increased DNA damage and lethality in cancer cells and activation of immune stimulatory mechanisms. CV6-168 does not inhibit dihydropyrimidine dehydrogenase, the rate-limiting enzyme responsible for 5-FU catabolism avoiding fluoropyrimidine drug-drug interactions and complex dose modifications. This is a first-in-human, modular study initially investigating PK and safety of CV6-168 with bolus/infusional 5-fluorouracil (5-FU) and folinic acid (FA). Methods: Primary objective: characterise safety and tolerability of CV6-168 with 5-FU and FA. Secondary objectives: establish PK profile of CV6-168 and 5-FU alone and in combination and evaluate anti-tumour activity of the combination. Exploratory objectives: investigate multiple surrogate, tumour and circulating pharmacodynamic assays related to mechanism of action and predictive biomarkers for CV6-168 and 5-FU. Each module of this study investigates a different hypothesis, driven by emerging data. Module 1, investigating CV6-168/5-FU/FA, consists of Part A (dose escalation in up to 51 pts) where the maximum tolerated/feasible dose will be identified to guide dose optimisation; Part B, proof of concept [PoC] expansions and identification of the recommended Phase 2 dose/schedule; and optional Parts C (dose optimisation cohorts) and D (basket cohort expansions). Part A is a “3 + 3” dose escalation design in pts with incurable advanced solid tumours and Part B expansions, powered to compare response rates to historical data, will include 3 cohorts of different tumour types. Part C is a randomised comparison of 2 doses/schedules to be selected based on Part A and B data, with pt populations selected based on emerging data. Further Modules may explore: Combination of CV6-168/5-FU/FA with a PD-(L)1 inhibitor; Combinations with other standard of care treatments; Food effects on CV6-168 bioavailability; and Different CV6-168 formulations. This trial design 1) Allows one protocol responsive to emerging data for a compound with multiple hypotheses, supporting studies in multiple combinations, reducing time from emerging data to ‘first subject in study" compared with multiple individual studies; 2) Has the potential to reduce the number of pts unnecessarily exposed to a novel agent; and 3) Allows investigators to pre-empt emerging data and changes to the treatment landscape. These challenges in oncology drug development emphasize the need for flexible designs as the landscape of drug development continually evolves. Clinical trial information: ISRCTN12434145.

Supplementary Excel_nCounter PanCancer Human Pathways Panel Gene List