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

Background

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.

Methods

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.

Results

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 C_max, 2.4-fold for AUC_0-t and 2.7-fold for AUC_0-∞] with ITZ co-administration. This correlated with reduced clearance (CL) by 63% and prolonged elimination half-life (t_1/2) 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 AUC_0-t and AUC_0-∞, respectively compared to LRB alone. Unbound LRB CL decreased by 58% and t_1/2 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.

Conclusions

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.

Clinical trial identification

NCT05063318.

Editorial acknowledgement

Legal entity responsible for the study

PharmaMar.

Funding

PharmaMar.

Disclosure

E. Calvo: Financial Interests, Personal, Advisory Board: Adcendo, Amunix, Anaveon, AstraZeneca, BMS, Janssen, MonTa, MSD, Nanobiotix, Nouscom, Novartis, Servier, TargImmune, T-knife, Chugai, Elevation Oncology, Ellipses Pharmacy, SyneosHealth, Genmab, Diaccurate; Financial Interests, Personal, Invited Speaker: OncoDNA, PharmaMar, Roche/Genentech; Financial Interests, Personal, Full or part-time Employment, Director, Clinical Research: HM Hospitales Group; Financial Interests, Personal, Full or part-time Employment, Medical Oncologist. Clinical Investigator. Director, Clinical Research: START Madrid-CIOCC (Centro Integral Oncológico Clara Campal); Financial Interests, Personal, Member of Board of Directors, External Independent member of Board of Directors: PharmaMar; Financial Interests, Personal, Ownership Interest: START, Oncoart Associated; Financial Interests, Personal, Steering Committee Member, Member of Data Monitoring Committee: BeiGene, Sanofi, Merus; Financial Interests, Personal, Steering Committee Member: Novartis; Non-Financial Interests, Other, Non-for-profit Foundation. President and co-founder: INTHEOS (Investigational Therapeutics in Oncological Sciences) non-for-profit Foundation; Non-Financial Interests, Advisory Role: PsiOxus; Non-Financial Interests, Other, Chair of the Independent Data Monitoring Committee: EORTC IDMC; Non-Financial Interests, Member of Board of Directors, Non-for-profit Foundation, trustee member: Non-for-profit Foundation PharmaMar; Non-Financial Interests, Advisory Role, Non-for-profit foundation: CRIS Cancer Foundation, non-for-profit ; Non-Financial Interests, Member: ASCO, ESMO, SEOM, EORTC. S. Fudio: Financial Interests, Personal, Stocks or ownership: PharmaMar. C. Kahatt, J. Iglesias, R.O. Calafati, L. Pérez Ramos, L. Montilla, A. Zeaiter, R. Lubomirov: Financial Interests, Stocks or ownership: PharmaMar. All other authors have declared no conflicts of interest.