Effect of Pevonedistat, an Investigational NEDD8-Activating Enzyme Inhibitor, on the QTc Interval in Patients With Advanced Solid Tumors

The purpose of this study was to assess the effect of pevonedistat, a neural precursor cell expressed, developmentally down-regulated protein 8 (NEDD8)-activating enzyme inhibitor, on the heart rate-corrected QT (QTc) interval in cancer patients. Patients were randomized 1:1 to receive pevonedistat 25 or 50 mg/m(2) on day 1 and the alternate dose on day 8. Triplicate electrocardiograms were collected at intervals over 0-11 hours and at 24 hours via Holter recorders on days -1 (baseline), 1, and 8. Changes from time-matched baseline values were calculated for QTc by Fridericia (QTcF), PR, and QRS intervals. Serial time-matched blood samples for analysis of pevonedistat plasma pharmacokinetics were collected and a concentration-QTc analysis conducted. Safety was assessed by monitoring vital signs, physical examinations, and clinical laboratory tests. Forty-four patients were included in the QTc analysis. Maximum least square (LS) mean increase from time-matched baseline in QTcF was 3.2 milliseconds at 1 hour postdose for pevonedistat at 25 mg/m(2) , while the LSs mean change from baseline in QTcF was -1.7 milliseconds 1 hour postdose at 50 mg/m(2) . The maximum 2-sided 90% upper confidence bound was 6.7 and 2.9 milliseconds for pevonedistat at 25 and 50 mg/m(2) , respectively. Pevonedistat did not result in clinically relevant effects on heart rate, nor on PR or QRS intervals. Results from pevonedistat concentration-QTc analysis were consistent with these findings. Administration of pevonedistat to cancer patients at a dose of up to 50 mg/m(2) showed no evidence of QT prolongation, indicative of the lack of clinically meaningful effects on cardiac repolarization. ClinicalTrials.gov identifier: NCT03330106 (first registered on November 6, 2017)

A Phase i Study of an MPS1 Inhibitor (BAY 1217389) in Combination with Paclitaxel Using a Novel Randomized Continual Reassessment Method for Dose Escalation

Purpose: Monopolar spindle 1 (MPS1) kinase inhibitor, BAY 1217389 (BAY) synergizes with paclitaxel. This phase I study assessed the combination of BAY with paclitaxel using a novel randomized continuous reassessment method (rCRM) to improve dose determination. Patients and Methods: Patients with solid tumors were randomized to receive oralBAY(twice daily 2-days-on/5-days-off) withweekly paclitaxel (90 mg/m2) or paclitaxel monotherapy in cycle 1. Dose escalation was guided by CRM modeling. Primary objectives were to assess safety, establish the MTD of BAY, and to evaluate the pharmacokinetic profiles for both compounds. Simulations were performed to determine the contribution of the rCRM for dose determination. Results: In total, 75 patients were enrolled. The main doselimiting toxicities were hematologic toxicities (55.6%). The MTD of BAY was established at 64 mg twice daily with paclitaxel. Inclusion of a control arm enabled the definitive attribution of grade ≥3 neutropenia to higher BAY exposure [AUC0-12 (P< 0.001)]. After determining the MTD, we included 19 patients with breast cancer at this dose for dose expansion. Other common toxicities were nausea (45.3%), fatigue (41.3%), and diarrhea (40.0%). Overall confirmed responses were seen in 31.6% of evaluable patients. Simulations showed that rCRM outperforms traditional designs in determining the true MTD. Conclusions: The combination of BAY with paclitaxel was associated with considerable toxicity without a therapeutic window. However, the use of the rCRM design enabled us to determine the exposure-toxicity relation for BAY. Therefore, we propose that the rCRM could improve dose determination in phase I trials that combine agents with overlapping toxicities. _2021 American Association for Cancer Research