Magnesium Supplementation in Advanced Non-small Cell Lung Cancer (NSCLC)

This randomized, double-blind, placebo-controlled, multicenter phase II/III trial evaluates the efficacy and safety of intravenous and oral magnesium supplementation in addition to standard first-line chemo-immunotherapy in patients with unresectable stage III or metastatic stage IV non-small cell lung cancer (NSCLC). Platinum-based chemotherapy frequently induces hypomagnesemia, which may impair T-cell mediated anti-tumor immunity and reduce the effectiveness of immune checkpoint inhibitors. This trial investigates whether correcting magnesium deficiency can enhance immune response and improve clinical outcomes. The primary objective of the phase II portion is to assess the safety and feasibility of magnesium supplementation and its impact on PFS. If interim analysis confirms tolerability without significant additional toxicity, the trial will seamlessly expand into a phase III component with overall survival (OS) as the primary endpoint. Secondary objectives include objective response rate (ORR), duration of response (DoR), adverse events (AEs) and serious adverse events (SAEs), health-related quality of life (HRQoL), immune-related biomarkers and magnesium levels. Patients are randomized to receive either: * Magnesium Arm: Standard chemo-immunotherapy + oral magnesium aspartate hydrochloride (3x/day) + intravenous magnesium sulfate on chemo days * Placebo Arm: Standard chemo-immunotherapy + matching placebo Magnesium levels are centrally monitored via plasma and urine samples. Anti-cancer therapy follows standard of care. 230 patients will be enrolled (70 in phase II, 160 in phase III). Eligible patients have stage IIIB/IV NSCLC, ECOG 0-1, and are scheduled for first-line chemo-immunotherapy. Key exclusions include eligibility for monotherapy, severe hypomagnesemia, or ongoing magnesium supplementation for other indications. Statistical and Quality Considerations The adaptive design includes an interim analysis for safety and a futility analysis for OS. Time-to-event and binary outcomes will be analyzed using standard statistical methods. Quality assurance includes eCRFs with validation checks, source data verification, SOPs, and risk-based monitoring. Although not formally a registry, the trial employs registry-like quality control elements: * Data validation: Real-time data entry into electronic case report forms (eCRFs) with predefined logic and range checks. * Source Data Verification (SDV): Conducted to ensure data accuracy and completeness via comparison with medical records and source documents. * Standard Operating Procedures: SOPs are implemented, which cover all trial operations-site initiation, data collection, patient assessments, safety reporting, and amendment handling. * Monitoring and auditing: Central and on-site monitoring according to a risk-based monitoring plan. Sites may be audited for compliance with ICH-GCP. This trial addresses a novel and biologically plausible mechanism of resistance to immunotherapy in NSCLC. By targeting chemotherapy-induced hypomagnesemia, the study explores a low-cost, scalable intervention with the potential to enhance immune-mediated tumor control. If successful, magnesium supplementation could represent a paradigm shift in the supportive care of patients receiving chemo-immunotherapy for advanced NSCLC.