A RANDOMIZED, CROSSOVER STUDY TO EVALUATE THE EFFECTS OF PEVONEDISTAT ON THE QTC INTERVAL IN PATIENTS WITH ADVANCED MALIGNANCIES
Author(s): ,
Xiaofei Zhou
Affiliations:
Millennium Pharmaceuticals Inc., a wholly owned subsidiary of Takeda Pharmaceutical Company Limited,Cambridge, MA,United States
,
Debra Richardson
Affiliations:
Stephenson Cancer Center at University of Oklahoma Health Sciences Center and Sarah Cannon Research Institute,Oklahoma City, OK,United States
,
Afshin Dowlati
Affiliations:
Case Western Reserve University,Cleveland, OH,United States
,
Sanjay Goel
Affiliations:
Montefiore Medical Center,Bronx, NY,United States
,
Solmaz Sahebjam
Affiliations:
University of South Florida H. Lee Moffitt Cancer Center and Research Institute,Tampa, FL,United States
,
James Strauss
Affiliations:
Mary Crowley Medical Research Centers,Dallas, TX,United States
,
Sant Chawla
Affiliations:
Sarcoma Oncology Center,Santa Monica, CA,United States
,
Ding Wang
Affiliations:
Henry Ford Hospital,Detroit, MI,United States
,
Vivek Samnotra
Affiliations:
GlaxoSmithKline Research and Development,Waltham, MA,United States
,
Douglas V. Faller
Affiliations:
Millennium Pharmaceuticals Inc., a wholly owned subsidiary of Takeda Pharmaceutical Company Limited,Cambridge, MA,United States
,
Karthik Venkatakrishnan
Affiliations:
Millennium Pharmaceuticals Inc., a wholly owned subsidiary of Takeda Pharmaceutical Company Limited,Cambridge, MA,United States
Neeraj Gupta
Affiliations:
Millennium Pharmaceuticals Inc., a wholly owned subsidiary of Takeda Pharmaceutical Company Limited,Cambridge, MA,United States
(Abstract release date: 05/14/20) EHA Library. Zhou X. 06/12/20; 294752; EP835
Xiaofei Zhou
Xiaofei Zhou
Contributions
Abstract

Abstract: EP835

Type: e-Poster

Background
Pevonedistat, the first and only NEDD8-activating enzyme inhibitor, interferes with protein homeostasis by preventing proteasomal degradation of selected proteins, leading to cancer cell death. It is currently in phase 3 clinical development in patients (pts) with higher-risk myelodysplastic syndromes, chronic myelomonocytic leukemia and acute myelogenous leukemia, in which pevonedistat 20 mg/m2 is dosed by intravenous infusion on Days 1, 3 and 5 in combination with azacitidine for 7 days in a 21-day cycle.

Aims
The primary objective of this study was to characterize the effects of 25 and 50 mg/m2 pevonedistat on the Fridericia corrected QT interval (QTcF) of the electrocardiogram (ECG).

Methods
Pts were adults with advanced malignancies and ECOG PS 0/1, who underwent continuous 12-lead digital ECG (Holter) monitoring for serial collections of triplicate ECGs on Days 1, 2, 8 and 9 and time-matched blood pharmacokinetic (PK) samplings, following a single-dose infusion of pevonedistat at 25 or 50 mg/m2 on Day 1 and Day 10 alternatively. The pevonedistat dose of 25 mg/m2 provided exposure coverage for combination with other standard-of-care chemotherapy agents, and a dose of 50 mg/m2 was the recommended phase 2 dose for pevonedistat as a single agent, dosed at 1, 3 and 5 days in a 21-day cycle. Triplicate ECGs collected on day -1 served as time-matched baseline. ECG data were centrally read. The primary endpoint was change from time-matched baseline in QTcF following single-dose administration of pevonedistat at 25 or 50 mg/m2. Secondary endpoints included: change from time-matched baseline in the individually corrected QTc interval (QTcI), in heart rate (HR), and pevonedistat PK. PK parameters, including peak concentration (Cmax) and area under the curve (AUC), were calculated using noncompartmental analysis. The relationship between pevonedistat concentration and change from time-matched baseline QTc endpoints was evaluated by mixed-effects modelling.

Results
44 pts were enrolled: 30% male; 75% white; median age, 62 years; mean weight, 75 kg. 43 pts were considered evaluable for ECG assessments. Following intravenous infusion of pevonedistat, the mean half-life of pevonedistat was 7 hours. Geometric mean Cmax was 197 and 509 ng/mL at 25 and 50 mg/m2, respectively. Geometric mean for AUC was 1310 and 2660 h*ng/mL at 25 and 50 mg/m2, respectively. Maximum 2-sided 90% upper confidence bound (UCB) of change from the time-matched baseline for QTcF was 6.7 and 2.8 msec at 25 and 50 mg/m2, respectively. Maximum 2-sided 90% UCB of change from the time-matched baseline for QTcI was 8.8 and 6.8 msec at 25 and 50 mg/m2, respectively. The 2-sided 90% lower confidence bound of change from the baseline for HR was -5.3 and -4.8 bpm at 25 and 50 mg/m2, respectively. The maximum upper bound of change in HR was 7.7 and 10.9 bpm at 25 and 50 mg/m2, respectively. By categorical analysis, a change in QTcF >30 msec was observed in 4 pts (9.5%) at 25 mg/m2. No patients at 50 mg/m2 experienced changes in QTcF >30 msec. There were no appreciable differences between the two dose levels and no trends were noted for variation in change of QTcF from baseline across the time points. Results from pevonedistat concentration-QTc analyses were consistent with those from the statistical analyses in supporting a lack of effect of pevonedistat on the QT intervals.

Conclusion
Administration of pevonedistat at a dose of up to 50 mg/m2 to patients with cancer showed no evidence of QT prolongation, indicative of the lack of clinically meaningful effects on cardiac repolarization.

Session topic: 10. Myelodysplastic syndromes - Clinical

Keyword(s): AML, Myelodysplasia, Safety

Abstract: EP835

Type: e-Poster

Background
Pevonedistat, the first and only NEDD8-activating enzyme inhibitor, interferes with protein homeostasis by preventing proteasomal degradation of selected proteins, leading to cancer cell death. It is currently in phase 3 clinical development in patients (pts) with higher-risk myelodysplastic syndromes, chronic myelomonocytic leukemia and acute myelogenous leukemia, in which pevonedistat 20 mg/m2 is dosed by intravenous infusion on Days 1, 3 and 5 in combination with azacitidine for 7 days in a 21-day cycle.

Aims
The primary objective of this study was to characterize the effects of 25 and 50 mg/m2 pevonedistat on the Fridericia corrected QT interval (QTcF) of the electrocardiogram (ECG).

Methods
Pts were adults with advanced malignancies and ECOG PS 0/1, who underwent continuous 12-lead digital ECG (Holter) monitoring for serial collections of triplicate ECGs on Days 1, 2, 8 and 9 and time-matched blood pharmacokinetic (PK) samplings, following a single-dose infusion of pevonedistat at 25 or 50 mg/m2 on Day 1 and Day 10 alternatively. The pevonedistat dose of 25 mg/m2 provided exposure coverage for combination with other standard-of-care chemotherapy agents, and a dose of 50 mg/m2 was the recommended phase 2 dose for pevonedistat as a single agent, dosed at 1, 3 and 5 days in a 21-day cycle. Triplicate ECGs collected on day -1 served as time-matched baseline. ECG data were centrally read. The primary endpoint was change from time-matched baseline in QTcF following single-dose administration of pevonedistat at 25 or 50 mg/m2. Secondary endpoints included: change from time-matched baseline in the individually corrected QTc interval (QTcI), in heart rate (HR), and pevonedistat PK. PK parameters, including peak concentration (Cmax) and area under the curve (AUC), were calculated using noncompartmental analysis. The relationship between pevonedistat concentration and change from time-matched baseline QTc endpoints was evaluated by mixed-effects modelling.

Results
44 pts were enrolled: 30% male; 75% white; median age, 62 years; mean weight, 75 kg. 43 pts were considered evaluable for ECG assessments. Following intravenous infusion of pevonedistat, the mean half-life of pevonedistat was 7 hours. Geometric mean Cmax was 197 and 509 ng/mL at 25 and 50 mg/m2, respectively. Geometric mean for AUC was 1310 and 2660 h*ng/mL at 25 and 50 mg/m2, respectively. Maximum 2-sided 90% upper confidence bound (UCB) of change from the time-matched baseline for QTcF was 6.7 and 2.8 msec at 25 and 50 mg/m2, respectively. Maximum 2-sided 90% UCB of change from the time-matched baseline for QTcI was 8.8 and 6.8 msec at 25 and 50 mg/m2, respectively. The 2-sided 90% lower confidence bound of change from the baseline for HR was -5.3 and -4.8 bpm at 25 and 50 mg/m2, respectively. The maximum upper bound of change in HR was 7.7 and 10.9 bpm at 25 and 50 mg/m2, respectively. By categorical analysis, a change in QTcF >30 msec was observed in 4 pts (9.5%) at 25 mg/m2. No patients at 50 mg/m2 experienced changes in QTcF >30 msec. There were no appreciable differences between the two dose levels and no trends were noted for variation in change of QTcF from baseline across the time points. Results from pevonedistat concentration-QTc analyses were consistent with those from the statistical analyses in supporting a lack of effect of pevonedistat on the QT intervals.

Conclusion
Administration of pevonedistat at a dose of up to 50 mg/m2 to patients with cancer showed no evidence of QT prolongation, indicative of the lack of clinically meaningful effects on cardiac repolarization.

Session topic: 10. Myelodysplastic syndromes - Clinical

Keyword(s): AML, Myelodysplasia, Safety

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