679P Lurbinectedin (LRB) pharmacokinetics (PK) and safety when co-administered with itraconazole (ITZ) in patients with advanced solid tumor

LRB is a highly selective inhibitor of oncogenic transcription primarily metabolized by CYP3A4. This study investigated whether the PK and safety profile of LRB is affected by co-administration with ITZ, a strong CYP3A4 inhibitor, in adult patients with advanced solid tumors. This was a 2-part crossover, open-label, phase Ib drug-drug interaction study (NCT05063318). In Part A, 3 patients were assigned to sequence 1 (TR) receiving a cycle (C) 1 of LRB (0.8 mg/m2, 1 hour [h], iv) co-administered with ITZ (200 mg/day oral; 12-days), followed by a C2 of LRB alone (3.2 mg/m2, 1 h, iv). In Part B, 11 patients were randomized (1:1) to receive either sequence 1 (TR) or 2 (RT). Plasma samples for LRB and ITZ PK were collected. 11 patients were evaluable for the primary objective of the study: 3 patients in Part A and 8 patients in Part B (4 in each of sequences 1 and 2). The systemic exposure of LRB was increased [15% for Cmax, 2.4-fold for AUC0-t and 2.7-fold for AUC0-∞] with ITZ co-administration. This correlated with reduced clearance (CL) by 63% and prolonged elimination half-life (t1/2) by 2.2-fold. Co-administration with ITZ produced statistically significant modifications in the unbound plasma LRB PK parameters of similar extent than in total plasma with a 2.2-fold and 2.4-fold increase in AUC0-t and AUC0-∞, respectively compared to LRB alone. Unbound LRB CL decreased by 58% and t1/2 was 2-fold longer. Consistent with previous studies, the most common treatment-related adverse events of LRB alone at dose of 3.2 mg/m2 were neutropenia, nausea, vomiting and fatigue. Safety profile of LRB at a dose of 0.9 mg/m2 when co-administered with ITZ was no worse than that of LRB administered alone at 3.2 mg/m2. In comparison with LRB alone, the co-administration with multiple doses of ITZ, significantly altered LRB systemic exposure reducing total plasma (by 63%) and unbound (by 58%) LRB CL. The magnitude of these changes showed a clinically relevant effect of ITZ co-administration on LRB PKs. To avoid LRB overexposure and a worst safety profile when co-administered with strong CYP3A4 inhibitors a LRB dose reduction proportional to CL reduction should be applied.