RAISIC-1: A phase 1/2 clinical trial of the GPR65 inhibitor PTT-4256—Preliminary safety, tolerability, pharmacokinetic, and pharmacodynamic results.

Abstract

2608 Background: The acidic tumor micro-environment is linked to immune suppression and insensitivity to immunotherapy. The G protein-coupled receptor, GPR65, is activated in this low pH environment, driving the increased transcription of myeloid immune-suppressive genes and reduced transcription of T- and NK-cell functional and effector genes. Against the backdrop of this target validation, PTT-4256, a first-in-class, potent, orally-bioavailable, allosteric, small molecule inhibitor of GPR65, is being developed as a potential treatment of solid tumors. In mouse syngeneic cancer models, oral administration of PTT-4256 as monotherapy delivers pronounced efficacy, which is enhanced in combination with an anti-PD-1 antibody. Transcriptomic analysis shows that PTT-4256 effectively reverses the acidic immune suppression in mice tumors. Methods: RAISIC-1 is a multi-modular Phase 1/2 clinical trial in adults with histologically confirmed advanced/metastatic solid malignancies who have previously received standard of care therapies. Phase 1 (Module A) is aimed to evaluate safety (treatment emergent and related adverse events – TEAE/TRAE; dose limiting toxicity – DLT; maximum tolerated dose-MTD), pharmacokinetics, pharmacodynamics, preliminary efficacy (as per RECIST 1.1) and estimate the optimal biological dose (OBD) / recommended Phase 2 dose (RP2D). PTT-4256 is administered orally in 21-day cycles until disease progression or unacceptable toxicity. A comprehensive biomarker program is included to detect immune-related changes in blood/plasma. Results: As of 7 January 2026, 14 participants (3 ongoing) have been treated with one of 5 dose-levels (10, 20, 40, 80 and 160 mg/day). PTT-4256 was well-tolerated with no DLTs. TRAEs were reported in ten participants, with fatigue (n = 8), nausea (n = 4), rash (n = 4), reduced appetite (n = 4), vomiting (n = 2) reported in more than 1 participant. All were grade 1 or 2 except one transient episode ( < 1 day) of grade 3 hypertension. Tumor shrinkage and stable disease have been observed at doses 40mg and above in six participants, of which two (nasopharyngeal cancer and renal cell cancer (RCC)) are ongoing in treatment > 5 months. Transcriptomics and proteomics analyses show dose-dependent changes in immune-related markers in blood/plasma following PTT-4256 treatment that are consistent with preclinical data and the mode of action. Conclusions: Enrollment at dose levels ≥ 300 mg is ongoing. Phase 2 (Module B) as PTT-4256 monotherapy or in combination with anti-PD1 in RCC and head & neck squamous cell cancer (HNSCC) will commence upon identification of RP2D. Clinical trial information: NCT06634849 .