PI-030 - EFFECT OF VALEMETOSTAT ON THE PHARMACOKINETICS OF MIDAZOLAM AND DIGOXIN (CYP3A AND P-GP SUBSTRATES): A PHASE 1 DRUG-DRUG INTERACTION STUDY IN PATIENTS WITH REFRACTORY OR RELAPSED NON-HODGKIN LYMPHOMA.

M. Tachibana¹, S. Horwitz², E. Jacobsen³, S. Inaba¹, Y. Iko¹, Y. Kakurai¹, N. Kitami¹, Y. Chen⁴, Y. Lau⁴; ¹Daiichi Sankyo, Tokyo, Japan, ²Memorial Sloan Kettering Cancer Center, New York, NY, USA, ³Dana-Farber Cancer Institute, Boston, MA, USA, ⁴Daiichi Sankyo, Basking Ridge, NJ, USA.

Background: Valemetostat is an oral, dual inhibitor of enhancer of zeste homolog (EZH) 2 and EZH1, approved in Japan for the treatment of relapsed or refractory (R/R) adult T-cell leukemia/lymphoma and peripheral T-cell lymphomas. It is being investigated for treatment of various types of cancer, including non-Hodgkin lymphomas (NHLs) and solid tumors. In vitro, valemetostat acts as an inhibitor of cytochrome P450 3A (CYP3A) and P-glycoprotein (P-gp) when combined with sensitive CYP3A or P-gp substrates, such as midazolam or digoxin, respectively. This phase 1 drug–drug interaction (DDI) study evaluated the effect of valemetostat on the pharmacokinetics (PK) of a sensitive CYP3A substrate (midazolam) and a sensitive P-gp substrate (digoxin) in patients with NHL.

Methods: Eligible adult patients with confirmed R/R B- or T-cell NHL received valemetostat (200 mg/day) in continuous 28-day treatment cycles and single doses of midazolam (2 mg) and digoxin (0.25 mg) on days –4 and 15 of cycle 1. The primary study objective was to assess the effect of multiple valemetostat doses on the PK of single-dose midazolam and digoxin when coadministered simultaneously in patients with NHL, during the first valemetostat-treatment cycle. The secondary objective was to assess the safety and tolerability of multiple valemetostat doses when coadministered with a single dose of midazolam and digoxin in patients with NHL.

Results: Twenty-four patients were enrolled, and 15 and 16 patients were evaluable for PK analyses of midazolam and digoxin, respectively. Coadministration of valemetostat with midazolam and digoxin slightly decreased midazolam Cmax and AUClast and increased digoxin exposure parameters (Table). The most common (≥ 40% of patients) adverse events (AEs) were dysgeusia, anemia, diarrhea, and platelet count decreased. Most common Grade ≥ 3 AEs were anemia, neutrophil count decreased, and platelet count decreased.

Conclusion: The findings from this DDI study indicate that valemetostat has no clinically meaningful DDI with sensitive CYP3A substrates, and has a potentially weak DDI ( < 30% increase) with sensitive P-gp substrates. Valemetostat demonstrated a manageable and tolerable safety profile when coadministered with midazolam and digoxin.