First-in-human evidence of multidrug resistance reversal in solid tumors: a cohort analysis of carbon nanoparticles‑Fe(II) complex trials

BACKGROUND: into tumor cells to induce ferroptosis. In this cohort analysis from a Phase I trial, we aim to evaluate the safety, imaging response, survival outcomes, and potential restoration of sensitivity to systemic therapies. METHODS: Nineteen patients in a Phase I study (NCT06048367) received the intratumoral injection of CNSI-Fe. The primary outcomes were safety and tolerability; secondary outcomes included radiographic response assessed by revised RECIST v1.1, tumor biology evaluated by necrosis and tumor growth rate (TGR), and long-term survival. All patients were followed after withdrawal from the study therapy. RESULTS: CNSI-Fe demonstrated an acceptable safety profile. CNSI-Fe consistently induced marked central necrosis on imaging despite minimal revised RECIST v1.1 shrinkage. Four patients (4/19, 21.1%) with heavily pretreated, progressive disease (ovarian serous carcinoma, pancreatic adenocarcinoma, myoepithelioma-like tumor of the vulvar region, and thyroid carcinoma) achieved long-term survival for 28.9-36.2 months post CNSI-Fe injection, accompanied by restored response to chemotherapies or targeted agents to which they were previously resistant (e.g., resensitization-restored sensitivity, hypersensitization-enhanced sensitivity). These four patients (4/19, 21.1%) demonstrated renewed sensitivity to subsequent systemic therapies (e.g., paclitaxel, carboplatin, bevacizumab, irinotecan liposome, and lenvatinib). CONCLUSIONS: This case series provides preliminary clinical evidence that CNSI-Fe could weaken MDR and resensitize solid tumors to systemic therapy. These findings warrant biomarker-integrated expansion cohorts and Phase II trials of CNSI-Fe-based combinations with radiotherapy, chemotherapy, targeted therapy, and immunotherapy. TRIAL REGISTRATION: The clinical data were derived from a completed prospective, single-arm, dose-escalation first-in-human trial (The Center for Drug Evaluation of the National Medical Products Administration, Registration No.: CTR20222235, Approval date: September 1, 2022; ClinicalTrials.gov Identifier: NCT06048367, First submitted date: August 24, 2023; RRID: SCR_002309).