Unresectable Solid Tumors

This open-label, randomized Phase II trial evaluates whether sequential iodine-125 seed implantation followed by cryoablation improves local tumor control versus single-modality local therapy (125I seeds alone or cryoablation alone) in unresectable solid tumors. The study is based on a complementary treatment rationale: cryoablation provides rapid cytoreduction of the dominant tumor component, while 125I seed brachytherapy delivers sustained low-dose-rate irradiation that may better suppress residual viable tumor at the periphery and microscopic extension zones. The trial is designed to determine whether this spatial and temporal complementarity translates into superior local disease control without unacceptable toxicity. Participants will be randomized in parallel to one of three arms: (1) sequential 125I seed implantation followed by cryoablation within a protocol-defined interval, (2) 125I seed implantation alone, or (3) cryoablation alone. Treatment assignment is open label; imaging-based efficacy endpoints will be assessed using a standard blinded assessment process (blinded evaluators), according to protocol-defined criteria. The primary endpoint is local control rate (LCR) of prespecified target lesions and progression-free survival (PFS). Key secondary endpoints are local progression-free survival (LPFS), overall survival (OS), early pain response, technical success, target-lesion re-intervention rate, and safety (including grade ≥3 treatment-emergent adverse events, CTCAE v5.0). Exploratory analyses include dosimetry-outcome associations, imaging/radiomics biomarkers, and peripheral blood biomarker dynamics.

Nivolumab (and other agents affecting the anti-programmed death-1 \[anti-PD-1\] pathway) have demonstrated anti-tumor activity in multiple tumor types. Combinations of immune-oncology (IO) agents with complimentary mechanisms as well as radiation represent a promising strategy to improve response rates to immunotherapy and overcome resistance. In this phase I/Ib study, radiation will be used in combination with IO agents nivolumab and anti-IL-8 (BMS-986253) to assess toxicity by organ system and then assess the preliminary efficacy of the treatment regimen. In Part 1, the study will determine the safe doses of radiation by organ site in conjunction with nivolumab and BMS-986253. In Part 2, the treatment regimen will be investigated in melanoma, prioritizing acral melanoma, to describe the response rate to treatment as well as other clinical and safety outcomes. The study will also provide the opportunity to evaluate changes in the tumor microenvironment induced by the treatment.