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Background PTT-4256 is a first-in-class, potent, orally-bioavailable allosteric, small molecule inhibitor of the pH-sensing G protein-coupled receptor (GPCR), GPR65, expressed on tumour-infiltrating immune cells. In the tumour micro-environment (TME), which has an acidic (i.e. lower than surrounding normal tissue) pH, GPR65 is naturally activated, driving immune suppression. 1 Inhibition of GPR65 in the TME results in increased infiltration and activity of NK and T cells, producing a coordinated anti-tumour immune response. In nonclinical studies, PTT-4256 was shown to effectively reverse the low pH-induced and GPR65 mediated immunosuppression in immune cells, exhibited efficacy as monotherapy and in combination with anti-PD-1 in multiple mouse syngeneic cancer models.2 Modulation of genes involved in cancer immunity were reported in mouse models. Transcriptomics in non-human primates’ blood also showed significant changes in effector and myeloid cell gene signatures.Methods RAISIC-1 is a multi-modular Phase 1/2 clinical trial. The ongoing Module A is a first-in-human, dose escalation module to evaluate the safety, tolerability, pharmacokinetics (PK), pharmacodynamics (PD), and preliminary efficacy of PTT-4256 monotherapy in up to 30 participants with solid tumours.Adults with histologically confirmed advanced/metastatic solid malignancies who have previously received standard of care therapies are administered PTT-4256 orally in 21-day cycles until disease progression or unacceptable toxicity.Safety assessments comprise of dose-limiting toxicity (DLT; first 21-day cycle), treatment-emergent adverse events (TEAE), and determination of maximum tolerated dose (MTD). Efficacy is evaluated according to RECIST 1.1 criteria. Module A aims to estimate the optimal biological dose (OBD) and recommended Phase 2 dose (RP2D).Results As of 18 June 2025, 9 participants have been treated (4 ongoing) across four dose-levels (10, 20, 40 and 80 mg/day). PTT-4256 was well-tolerated and there were no DLTs. Treatment-related AEs were reported in six patients, fatigue (n=3), nausea/vomiting (n=3), rash (n=2), reduced appetite (n=2), dry retching (n=1), irritability (n=1), lethargy (n=1) and hypertension (n=1). All were grade 1 or 2 except one transient episode (<1day) of grade 3 hypertension. One patient (ongoing treatment > 3 months) achieved stable disease in first post-baseline assessment. Transcriptomic analysis of blood demonstrated increased expression of NK/T cell genes and reduced expression of myeloid genes, consistent with the preclinical results and mode of action of PTT-4256. Transcriptomics data from lactic acid-stimulated blood samples and plasma proteomics (Olink® Reveal) are being analysed.Conclusions Patient enrollment at dose levels 80 mg and above is ongoing, all available clinical safety, preliminary activity, PK and PD data will be presented.Trial Registration NCT06634849References Bohn T, Rapp S, Luther N, Klein M, Bruehl TJ, Kojima N, Aranda Lopez P, Hahlbrock J, Muth S, Endo S, Pektor S, Brand A, Renner K, Popp V, Gerlach K, Vogel D, Lueckel C, Arnold-Schild D, Pouyssegur J, Kreutz M, Huber M, Koenig J, Weigmann B, Probst HC, von Stebut E, Becker C, Schild H, Schmitt E, Bopp T. Tumor immunoevasion via acidosis-dependent induction of regulatory tumor-associated macrophages. Nat Immunol. 2018 Dec;19(12):1319–1329. doi: 10.1038/s41590-018-0226-8. Epub 2018 Nov 5. PMID: 30397348.Corbin A, et al. Abstract 497 PTT-4256 is a first-in-class small molecule inhibitor of GPR65 that counteracts the low pH-dependent immunosuppressive effects on immune cells and displays pronounced anti-tumor activity in mice. J. Immunother. Cancer 2023;11.Ethics Approval The study was approved by Bellberry Human Research Ethics Committee, ID number 2024-06-775, and Austin Health Human Research Ethics Committee, ID number VicTRI-19673. All participants provided informed consent prior to taking part in this clinical study.