Abstract: Novel implantable miniaturized devices (IMDs) placed directly in patient tumors can rapidly evaluate multi-drug responses in-situ. They can be used in any solid tumor to provide direct, comprehensive, spatial multi- omic readouts of >20 drugs simultaneously, with potential to eclipse liquid and tissue biopsy biomarker capabilities. However, placing and retrieving IMDs in tumors currently requires highly invasive surgery with excessively high patient morbidity and complication risks. For most cancer patients, these risks are prohibitive, and as a result ongoing first-in-human IMD trials have had limited enrollment. We have developed a fully interventional (minimally invasive) non-surgical method to place and retrieve IMDs. We use custom needle biopsy devices and image guidance to deliver and precisely remove only the IMD and adjacent drug-exposed tissue. This is a simple outpatient procedure similar to routine percutaneous tumor biopsies, using a single tiny (<2mm) skin incision. It reduces the morbidity and risks of IMD use, and would greatly increase enrollment in current and future clinical IMD trials. However, a preclinical study in an animal model is needed to demonstrate technical feasibility and safety of this interventional method prior to first-in- human use. This proposal describes a preclinical study in a rabbit hindlimb tumor model that closely simulates a typical soft tissue sarcoma setting, with the following specific aims: 1) determine the technical feasibility of our interventional (non-surgical) approach for IMD-placement and retrieval; and 2) determine the overall safety and adverse event rate of this same interventional method. Interventional IMD placement and retrieval procedures will be performed in a statistically-powered cohort of 15 rabbits. Technical feasibility and safety endpoints will be assessed, and used to inform further method refinement and ultimately first-in-human trials. The proposed study is innovative as it will develop and validate new interventional tools for personalized cancer treatment that could serve as the next generation of tumor biopsy. It is significant as it will directly enable a first-in-human trial to evaluate IMD-based drug optimization in patients with advanced soft tissue sarcomas. It will also enable greater enrollment in ongoing IMD clinical trials in other similar or lower risk anatomic regions (e.g. breast). Ultimately, if the overall long-term goal of clinically validating IMD-based personalized treatment optimization is achieved, the interventional methods developed here could be applicable to every oncology patient with a percutaneously accessible tumor (similar to routine percutaneous tissue biopsies).