Search

A fundamental issue in cancer drug development is the discordance between robust anti-tumor efficacy observed in laboratory models and the inadequate translation of these effects as clinical benefit to cancer patients. Imprecise modeling of tumor complexity and heterogeneity may underlie this problem. The CIVO platform, a research tool that simultaneously delivers drugs and drug combinations in microdose amounts to distinct, trackable tumor regions, was designed to address this disparity. Following FDA's exploratory IND guidelines for microdosing, this is a Phase 0, multi-center, single-arm, 12-patient study evaluating the highly localized pharmacodynamics (PD) in the native tumor microenvironment (TME) following intratumoral administration of subtherapeutic microdoses of the SUMOylation inhibitor TAK-981 (subasumstat) alone and in combination in subjects with HNSCC undergoing surgical resection. The safety of microdose administration via the CIVO device is also evaluated. This is the first clinical CIVO study evaluating an investigational agent and aims to provide insights into TAK-981's ability to modulate anti-tumor immune mechanisms, particularly induction of Type I interferon (IFN I) signaling. Eligible subjects have a confirmed diagnosis of HNSCC, ECOG 0-2, and planned surgical resection, with a surface-accessible tumor ≥ 2cm in the oral cavity or within cervical lymph nodes. The microdose injection consists of either vehicle, TAK-981, or combinations simultaneously administered via a 3-, 5-, or 8-needle device based on tumor size. Following surgical resection, tumor samples undergo evaluation via biomarker staining at a central site. The first cohort of patients underwent surgery 24-hours after injection. Enrollment of a 72-hour cohort is ongoing. As of Oct 2021, 7 subjects provided informed consent and were enrolled, with data available for 6 subjects, aged 42-80 years: 4 males and 2 females. Successful injections were visualized after the injection, during sample processing, and in biomarker-stained tissue sections via a fluorescent tracking marker co-injected through each needle. No adverse events associated with the injection procedure or microdoses have been reported. Biomarker analysis demonstrated TAK-981 distribution around the injection site accompanied by a reduction of SUMOylation, confirming pathway inhibition in patient tumors. Elevation of IFN I signaling was also observed in TAK-981 exposed areas within the TME. Initial study findings demonstrated the safety of CIVO microdosing in patients with surface-accessible HNSCC tumors. The analysis confirmed anticipated effects of TAK-981 within the TME, supporting the validity of CIVO as a translational oncology platform for early clinical evaluation of investigational agents. [ABSTRACT FROM AUTHOR]