Abstract CT206: A phase I open-label, dose escalation and expansion trial to investigate the safety, pharmacokinetics and pharmacodynamics of CB307, a trispecific Humabody T-cell enhancer, in patients with PSMA+ advanced and/or metastatic solid tumors (POTENTIA)

T cell redirecting therapy, including bispecific antibodies, is a proven anti-cancer treatment modality. Humabodies* are fully human VH antibody components that can be connected by a short peptide linker to make multi-specific molecules. Preclinical studies show that humabodies are distributed to tumors effectively and penetrate the tumor microenvironment efficiently compared with conventional monoclonal antibodies. CB307 is a tri-specific humabody targeting PSMA, CD137 and human serum albumin (HSA) where simultaneous binding to CD137 and PSMA elicits T-cell activation via CD137 agonism only in PSMA-expressing tumors. Binding to HSA ensures half-life extension and efficient systemic delivery of CB307 to the tumor. CD137 agonists promote T cell survival, proliferation and memory-like T cell formation, and are generally considered to be better tolerated than, for example, CD3 targeting agents regarding cytokine release syndrome. The objectives of the POTENTIA study are to determine the maximum tolerated dose (MTD) and pharmacokinetics of CB307 and to assess preliminary anti-tumor activity in PSMA+ solid tumor patients. Methods: The phase 1 study consists of dose escalation (part 1) and cohort expansion (part 2) components. The dose escalation uses an accelerated titration design (ATD) and a modified continual reassessment method (mCRM) to determine the MTD and the recommended phase 2 dose (RP2D). This adaptive design allows rapid dose escalation and helps to minimise the number of patients at suboptimal doses and to determine the MTD and RP2D accurately. Cohort expansion uses the same eligibility criteria, however, at least 3 patients with castration-resistant prostate cancer harbouring either BRCA1, BRCA2, ATM and/or CDK12 mutation(s) will be enrolled. A total of 50 patients overall with prospectively demonstrated PSMA tumor expression determined by immunohistochemistry will be enrolled to receive CB307 administered by weekly IV. PSMA-PET will also be taken at baseline for the assessment of systemic PSMA status. Key inclusion criteria are: histologically confirmed advanced or metastatic solid tumors; not amenable to standard-of-care therapy; RECIST measurable disease or increasing serum PSA at baseline for bone metastasis-only prostate cancer. Patients with brain metastases, patients who have discontinued previous immunotherapy due to intolerable immune-related adverse events and patients with acute infections or autoimmune diseases are excluded from the st