Targeted long-acting cisplatin–SRGel for enhanced chemoradiation in head and neck cancer: Preclinical pharmacokinetics, safety, and efficacy.

Abstract

e18077 Background: Systemic cisplatin combined with radiotherapy is the standard of care for unresectable head and neck squamous cell carcinoma (HNSCC), but its use is often limited by severe toxicities, including nephrotoxicity, and neurotoxicity, etc. As a result, many patients, particularly elderly individuals and those with comorbidities, are ineligible for optimal cisplatin-based chemoradiation and receive less effective alternatives. Contrary to the numerous localized cisplatin delivery approaches that have been explored, SRGel is a solvent-free, lipophilic, biodegradable long-acting injectable platform enabling high local drug payloads with sustained release via surface erosion for approximately two months. SRGel -Cisplatin formulation of 100 mg/mL (10% w/w), termed TumoCure, was selected for translational development. This abstract summarizes the preclinical pharmacokinetics, safety, and efficacy of TumoCure as monotherapy and in combination with radiotherapy, compared with systemic cisplatin. Methods: TumoCure was studied for intratumoral applications, safety and efficacy. Pharmacokinetics and safety were evaluated in Sprague–Dawley rats following a single subcutaneous dose of TumoCure and compared with systemic cisplatin. Plasma platinum levels were measured by ICP-MS, and toxicity was assessed by clinical observations, blood chemistry, and histopathology. Antitumor efficacy was evaluated as monotherapy in FaDu HNSCC xenografts, and compared to systemic cisplatin. Combination efficacy was assessed in multiple HNSCC models with fractionated radiotherapy. Results: TumoCure produced approximately one order of magnitude lower peak systemic platinum levels than intravenous cisplatin, with prolonged exposure and reduced renal toxicity. Histopathology showed minimal foreign-body reaction at low and intermediate doses, while higher local doses produced localized necrosis consistent with on-target cytotoxicity. TumoCure achieved higher intratumoral platinum concentrations than systemic cisplatin and delayed tumor growth in selected HNSCC models. In combination studies, TumoCure plus radiotherapy produced superior tumor growth inhibition compared with radiotherapy alone or radiotherapy with systemic cisplatin, without the systemic toxicity associated with standard chemoradiation. Conclusions: TumoCure is a long-acting cisplatin formulation enabling sustained local drug exposure with markedly reduced systemic toxicity. Preclinical data demonstrate favourable pharmacokinetics, improved safety, and enhanced efficacy as monotherapy and in combination with radiotherapy compared with systemic cisplatin. TumoCure is currently being evaluated in a Phase Ib clinical study in palliative and resistant disease settings, with a Phase II combination study with radiotherapy in preparation.