PHASE 1/1B STUDY OF PEVONEDISTAT (PEV) AS A SINGLE AGENT OR COMBINED WITH AZACITIDINE (AZA) IN EAST ASIAN PATIENTS (PTS) WITH ACUTE MYELOID LEUKEMIA (AML) OR MYELODYSPLASTIC SYNDROME (MDS)
Author(s): ,
Shang-Ju Wu
Affiliations:
National Taiwan University Hospital,Taipei,Taiwan, Province of China
,
June-Won Cheong
Affiliations:
Severence Hospital,Yonsei University Health System,Seoul,Korea, Republic Of
,
Yasushi Onishi
Affiliations:
National University,Corporation Tohoku University,Tohoku,Japan
,
Hiroatsu Iida
Affiliations:
National Hospital Organization,Nagoya Medical Center,Nagoya,Japan
,
Yukio Kobayashi
Affiliations:
International University of Health and Welfare, Mita Hospital,Tokyo,Japan
,
Hyeoung-Joon Kim
Affiliations:
Chonnam National University, Hwasun Hospital,Hwasun,Korea, Republic Of
,
Tzeon-Jye Chiou
Affiliations:
Taipei Veterans General Hospital,Taipei,Taiwan, Province of China
,
Xiaofei Zhou
Affiliations:
Millennium Pharmaceuticals Inc., a wholly owned subsidiary of Takeda Pharmaceutical Company Limited,Cambridge, MA,United States
,
Helene Faessel
Affiliations:
Millennium Pharmaceuticals Inc., a wholly owned subsidiary of Takeda Pharmaceutical Company Limited,Cambridge, MA,United States
,
Ying Yuan
Affiliations:
Millennium Pharmaceuticals Inc., a wholly owned subsidiary of Takeda Pharmaceutical Company Limited,Cambridge, MA,United States
,
Farhad Sedarati
Affiliations:
Millennium Pharmaceuticals Inc., a wholly owned subsidiary of Takeda Pharmaceutical Company Limited,Cambridge, MA,United States
,
Douglas V Faller
Affiliations:
Millennium Pharmaceuticals Inc., a wholly owned subsidiary of Takeda Pharmaceutical Company Limited,Cambridge, MA,United States
,
Akiko Kimura
Affiliations:
Takeda Pharmaceutical Company Limited,Osaka,Japan
Hiroshi Handa
Affiliations:
Gunma University Hospital,Maebashi,Japan
EHA Library. WU S. 06/16/18; 215321; PS997
SHANG-JU WU
SHANG-JU WU
Contributions
Abstract

Abstract: PS997

Type: Poster Presentation

Presentation during EHA23: On Saturday, June 16, 2018 from 17:30 - 19:00

Location: Poster area

Background
PEV, a first-in-class NEDD8-activating enzyme inhibitor, has demonstrated synergistic activity with AZA in preclinical AML models. The clinical safety and tolerability profile of PEV administered alone or in combination with AZA was shown in phase 1/1b studies of Western pts with AML/MDS.   

Aims
The primary objectives of this phase 1/1b trial (NCT02782468) were to assess safety/tolerability and pharmacokinetics (PK) of PEV as a single agent (PEV arm) or combined with AZA (PEV+AZA arm) and to determine the recommended phase 2/3 dose (RP2/3D) of PEV in the PEV+AZA arm in East Asian pts with AML/MDS. Response evaluation was a secondary objective.

Methods
This 3+3 dose escalation and expansion study enrolled adult East Asian pts with WHO-defined AML or higher-risk MDS (IPSS-R very high/high/intermediate risk). Pts receiving PEV had relapsed/refractory (R/R) AML/MDS and pts receiving PEV+AZA had R/R or untreated disease and were unfit for intensive chemotherapy. In the PEV arm, pts received PEV 25 or 44 mg/m2 IV on days 1, 3 and 5 (21 day cycle). Pts in the PEV+AZA arm received PEV 10 or 20 mg/m2 IV on days 1, 3 and 5 + AZA 75 mg/m2 IV or SC on days 1–5 and 8–9 (28 day cycle). Treatment was given until progressive disease or discontinuation for any reason. Informed consent was provided. PK samples were collected pre- and post-dose at various timepoints on days 1 and 5, and post-dose on days 2, 3, 6 and 7 of cycle 1. Best overall response was assessed by investigators according to International Working Group (IWG) criteria for AML or modified IWG criteria for MDS.

Results
As of 1-Nov-2017, 20 pts were enrolled in East Asian countries (safety population): 10 received single-agent PEV (25 mg/m2, n=3; 44 mg/m2, n=7) and 10 PEV+AZA (PEV 10 mg/m2, n=3; PEV 20 mg/m2, n=7); overall median treatment exposure was 3 (range: 1–19) cycles. Median age was 75 (range: 47–84) years in the PEV arm and 67 (range: 59–76) years in the PEV+AZA arm. In each arm, 9 pts (90%) were male, 4 (40%) had de novo AML, 4 (40%) had secondary AML (including 3 pts in the PEV arm and 2 pts in the PEV+AZA arm who had AML secondary to prior MDS) and 2 (20%) had de novo MDS. Most pts had received prior chemotherapy (13/16 AML and 3/4 MDS pts). There was 1 pt with dose-limiting toxicities in cycle 1 of grade 3 atrial fibrillation and grade 3 tumor lysis syndrome in the PEV 20 mg/m2 +AZA arm. PEV RP2/3D in the PEV+AZA arm was 20 mg/m2, identical to the RP2/3D determined for Western pts. All pts experienced grade ≥3 adverse events (AEs) (drug related in 4 PEV and 8 PEV+AZA pts). Nine (90%) PEV pts and 5 (50%) PEV+AZA pts had serious AEs, and 3 (30%) pts in each arm discontinued study due to AEs. Common any-grade AEs are shown in the Table. Three on-study deaths were reported (not treatment related): 1 PEV pt (AML) and 2 PEV+AZA pts (pneumonia; acute kidney injury). PEV PK were consistent with those observed in Western pts. In the PEV+AZA arm, all 5 evaluable AML pts (1 de novo, 1 relapsed/refractory, and 3 secondary AML) responded to treatment and 1 MDS pt had marrow CR. Responses were not observed in the PEV arm.

Conclusion
Single-agent PEV treatment in East Asian pts with AML/MDS appeared to be tolerable, with similar safety and PK profiles to those of Western pts. Addition of PEV to AZA did not result in additional toxicity and PEV RP2/3D was identical to that of Western pts. Substantial objective clinical responses were seen in East Asian pts with AML treated with PEV+AZA and were also consistent with those of Western pts with AML.

Session topic: 4. Acute myeloid leukemia - Clinical

Keyword(s): Acute Myeloid Leukemia, Myelodysplasia, Phase I

Abstract: PS997

Type: Poster Presentation

Presentation during EHA23: On Saturday, June 16, 2018 from 17:30 - 19:00

Location: Poster area

Background
PEV, a first-in-class NEDD8-activating enzyme inhibitor, has demonstrated synergistic activity with AZA in preclinical AML models. The clinical safety and tolerability profile of PEV administered alone or in combination with AZA was shown in phase 1/1b studies of Western pts with AML/MDS.   

Aims
The primary objectives of this phase 1/1b trial (NCT02782468) were to assess safety/tolerability and pharmacokinetics (PK) of PEV as a single agent (PEV arm) or combined with AZA (PEV+AZA arm) and to determine the recommended phase 2/3 dose (RP2/3D) of PEV in the PEV+AZA arm in East Asian pts with AML/MDS. Response evaluation was a secondary objective.

Methods
This 3+3 dose escalation and expansion study enrolled adult East Asian pts with WHO-defined AML or higher-risk MDS (IPSS-R very high/high/intermediate risk). Pts receiving PEV had relapsed/refractory (R/R) AML/MDS and pts receiving PEV+AZA had R/R or untreated disease and were unfit for intensive chemotherapy. In the PEV arm, pts received PEV 25 or 44 mg/m2 IV on days 1, 3 and 5 (21 day cycle). Pts in the PEV+AZA arm received PEV 10 or 20 mg/m2 IV on days 1, 3 and 5 + AZA 75 mg/m2 IV or SC on days 1–5 and 8–9 (28 day cycle). Treatment was given until progressive disease or discontinuation for any reason. Informed consent was provided. PK samples were collected pre- and post-dose at various timepoints on days 1 and 5, and post-dose on days 2, 3, 6 and 7 of cycle 1. Best overall response was assessed by investigators according to International Working Group (IWG) criteria for AML or modified IWG criteria for MDS.

Results
As of 1-Nov-2017, 20 pts were enrolled in East Asian countries (safety population): 10 received single-agent PEV (25 mg/m2, n=3; 44 mg/m2, n=7) and 10 PEV+AZA (PEV 10 mg/m2, n=3; PEV 20 mg/m2, n=7); overall median treatment exposure was 3 (range: 1–19) cycles. Median age was 75 (range: 47–84) years in the PEV arm and 67 (range: 59–76) years in the PEV+AZA arm. In each arm, 9 pts (90%) were male, 4 (40%) had de novo AML, 4 (40%) had secondary AML (including 3 pts in the PEV arm and 2 pts in the PEV+AZA arm who had AML secondary to prior MDS) and 2 (20%) had de novo MDS. Most pts had received prior chemotherapy (13/16 AML and 3/4 MDS pts). There was 1 pt with dose-limiting toxicities in cycle 1 of grade 3 atrial fibrillation and grade 3 tumor lysis syndrome in the PEV 20 mg/m2 +AZA arm. PEV RP2/3D in the PEV+AZA arm was 20 mg/m2, identical to the RP2/3D determined for Western pts. All pts experienced grade ≥3 adverse events (AEs) (drug related in 4 PEV and 8 PEV+AZA pts). Nine (90%) PEV pts and 5 (50%) PEV+AZA pts had serious AEs, and 3 (30%) pts in each arm discontinued study due to AEs. Common any-grade AEs are shown in the Table. Three on-study deaths were reported (not treatment related): 1 PEV pt (AML) and 2 PEV+AZA pts (pneumonia; acute kidney injury). PEV PK were consistent with those observed in Western pts. In the PEV+AZA arm, all 5 evaluable AML pts (1 de novo, 1 relapsed/refractory, and 3 secondary AML) responded to treatment and 1 MDS pt had marrow CR. Responses were not observed in the PEV arm.

Conclusion
Single-agent PEV treatment in East Asian pts with AML/MDS appeared to be tolerable, with similar safety and PK profiles to those of Western pts. Addition of PEV to AZA did not result in additional toxicity and PEV RP2/3D was identical to that of Western pts. Substantial objective clinical responses were seen in East Asian pts with AML treated with PEV+AZA and were also consistent with those of Western pts with AML.

Session topic: 4. Acute myeloid leukemia - Clinical

Keyword(s): Acute Myeloid Leukemia, Myelodysplasia, Phase I

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