092: Concentration-QTc Interim Analysis of I-DXd in Subjects With Advanced Solid Tumors from Study IDeate-Pantumor01 (DS7300-A-J101)

Statement of Purpose, Innovation or Hypothesis: I-DXd, a novel anti-B7-H3 targeting antibody drug conjugate (ADC) with an exatecan derivative payload, DXd, is being evaluated in the ongoing phase 1/2 dose-escalation and ‑expansion study IDeate-Pantumor01 (NCT04145622) in subjects with advanced solid malignant tumors. Results of human ether-a-go-go related gene (hERG) studies of DXd showed that DXd did not inhibit the hERG channel current.¹ The objectives of this interim concentration‑QTc (C-QTc) analysis were to: 1) characterize the relationship of change from baseline QTc interval (ΔQTc) with I-DXd plasma concentration and with DXd plasma concentration individually, and 2) predict concentration-related QTc interval prolongation (if any) with associated confidence interval (CI) at the therapeutic doses of interest, 8 and 12 mg/kg.

Description of Methods & Materials: Triplicate 12-lead ECGs and time-matched PK data across a dose range of 0.8–16 mg/kg IV Q3W were analyzed as of 26 January 2023. A prespecified linear mixed-effects model for change in QTc (ΔQTcF or ΔQTcP) was used. Model development began by confirming the significance of the baseline effect and the random effect on slope. Potential covariates, including demographic, electrolyte, and QT prolongation concomitant medications were tested as intercept effects in the model.

Data & Results: A population-specific correction was estimated to remove the slope of QTc versus RR interval (QTcP = QT/RR^p, where p was estimated at 0.393), as the Fridericia correction did not completely remove the slope. No evidence of hysteresis between concentrations and mean QTc was seen in concentration-QTc plots over time. Concentration-ΔQTc data plots showed no evidence of a nonlinear relationship, so linear mixed-effects modeling was used. In linear mixed-effects modeling of the four cases (ΔQTcF and ΔQTcP versus I‑DXd and versus DXd), the slope versus concentration relationship was significant for ΔQTcP versus DXd only, and it was negative. Baseline QTc had a significantly negative effect on ΔQTc in all models, while no other covariates were significant. Geometric mean C_max values for 8 and 12 mg/kg doses, from Cycle 3 (after multiple doses) of the study, were 197 and 304 µg/mL for I‑DXd and 3.85 and 6.05 ng/mL for DXd, respectively. Ninety percent CI upper bounds at these concentrations were predicted to reach at most −2.06 or −2.09 ms for I-DXd and −1.36 or −1.37 ms for DXd in the ΔQTcF and ΔQTcP models, respectively.

Interpretation, Conclusion or Significance: Ninety percent CI upper bounds of predicted mean ΔQTcF and ΔQTcP were negative for all doses, supporting a lack of a clinically meaningful effect on QTc interval for I‑DXd and DXd in this population. No demographic, electrolyte, or concomitant medication covariates had a significant relationship with QTc in this analysis. Based on currently available clinical safety data and this interim C-QTc analysis, there are no findings that raise concerns of QT prolongation.

Disclosures: BPT, NMM, NO, JD, MW, NY, SSV and YL are employed by Daiichi Sankyo Inc.  BP is employed by Certara Inc.

Citations/References: 1. ENHERTU. NDA/BLA multi-disciplinary review and evaluation (US Food and Drug Administration, Rockville, MD, 2019). https://www.accessdata.fda.gov/drugsatfda_docs/nda/2019/761139Orig1s000MultidisciplineR.pdf.

Additional Information/Authors: Authors: Brittany P. Tran1, Bill Poland2, Narasimha M. Midde1, Naoko Okamoto1, Jasmeet Singh1, Meng Qian1, Naoto Yoshizuka1, Soniya S. Vaidya1, Yvonne Lau1
Affiliations: 1Daiichi Sankyo, Inc., Basking Ridge, NJ, USA; 2Certara Inc., Princeton, NJ, USA