Contributions
Abstract: PB2099
Type: Publication Only
Background
Pevonedistat (PEV), a first-in-class NEDD8-activating enzyme inhibitor, combined with azacitidine (AZA) has demonstrated clinical activity in Western patients (pts) with acute myeloid leukemia (AML). PEV is currently in global clinical development for higher risk myelodysplastic syndromes (HR MDS), chronic myelomonocytic leukemia (CMML), and low-blast AML in a global phase 3 pivotal trial PANTHER (P3001).
Aims
To enable timely enrollment of Study P3001 for pts in East Asia, we proposed to apply multi-regional clinical trial (MRCT) principles of the ICH E17 draft guidelines informed by ICH E5 principles from an exploratory point of view to define the dose and minimum required number of East Asian pts in the pooled East Asian region.
Methods
Disease epidemiology, cytogenetic and mutational profiles of MDS, CMML, and AML among Caucasian and East Asian populations, treatment landscape, and efficacy of AZA were investigated. PEV pharmacokinetics (PK) and safety data in East Asian pts were collected in Pevonedistat-1012 (P1012), a phase 1 dose-finding study of PEV in combination with AZA conducted in Japan, South Korea, and Taiwan. Informed consent was provided for Study P1012. Population PK analyses were conducted to compare PEV exposures between East Asian and Western pts. Statistical considerations were provided to estimate the probabilities of consistency in efficacy between East Asian pts and the overall study population to be enrolled in the P3001 phase 3 study.
Results
According to epidemiological data reported by US, EU, Japan, and South Korea, the incidence of MDS and AML are comparable across these regions. Comparison of the molecular alterations in AML, MDS, and CMML across Caucasian and East Asian populations as well as the frequencies of these alterations suggested that the cytogenetic and mutational landscape is generally similar across these ethnicities. Literature research indicated that AZA shows comparable efficacy (response rate and hematologic improvement) in pts from Japan and South Korea. Preliminary PEV PK data from 18 pts (including 8 from Japan, 7 from Taiwan, and 3 from South Korea in Study P1012) indicated similar PEV PK profiles in East Asian (37%) and Western pts (geometric mean dose-normalized AUC48h of 1167 [CV of 37%] and 1065 h*ng/mL [CV of 32%], respectively). In addition, systemic PEV exposures were consistent across the major East Asian races (ie, Japanese, Korean, Chinese). The safety profile of PEV alone or in combination with AZA in East Asian pts was generally comparable to that observed in Western pts. Based on the assumption that the treatment effects in Japanese/East Asian pts are similar to those in the overall population, with a total of 30 East Asian pts, the estimated probabilities of achieving consistent efficacy outcomes (measured by event-free survival and overall survival) between East Asian pts and the overall 450 pts in the global pivotal trial P3001 are >80%.
Conclusion
Intrinsic and extrinsic factors relevant to disease (HR MDS, CMML, and low-blast AML) and PEV were inferred to be similar across the planned countries of enrollment in the pooled East Asian region (Japan, South Korea) and between East Asian and Western regions. Clinical efficacy and safety data from the P3001 phase 3 study are therefore applicable to inform benefit-risk assessment for the East Asian population and are additionally justified to be pooled across pts enrolled for purposes of assessing consistency in the benefit-risk profile in East Asian populations.
Session topic: 10. Myelodysplastic syndromes – Clinical
Keyword(s): Acute Myeloid Leukemia, Myelodysplasia
Abstract: PB2099
Type: Publication Only
Background
Pevonedistat (PEV), a first-in-class NEDD8-activating enzyme inhibitor, combined with azacitidine (AZA) has demonstrated clinical activity in Western patients (pts) with acute myeloid leukemia (AML). PEV is currently in global clinical development for higher risk myelodysplastic syndromes (HR MDS), chronic myelomonocytic leukemia (CMML), and low-blast AML in a global phase 3 pivotal trial PANTHER (P3001).
Aims
To enable timely enrollment of Study P3001 for pts in East Asia, we proposed to apply multi-regional clinical trial (MRCT) principles of the ICH E17 draft guidelines informed by ICH E5 principles from an exploratory point of view to define the dose and minimum required number of East Asian pts in the pooled East Asian region.
Methods
Disease epidemiology, cytogenetic and mutational profiles of MDS, CMML, and AML among Caucasian and East Asian populations, treatment landscape, and efficacy of AZA were investigated. PEV pharmacokinetics (PK) and safety data in East Asian pts were collected in Pevonedistat-1012 (P1012), a phase 1 dose-finding study of PEV in combination with AZA conducted in Japan, South Korea, and Taiwan. Informed consent was provided for Study P1012. Population PK analyses were conducted to compare PEV exposures between East Asian and Western pts. Statistical considerations were provided to estimate the probabilities of consistency in efficacy between East Asian pts and the overall study population to be enrolled in the P3001 phase 3 study.
Results
According to epidemiological data reported by US, EU, Japan, and South Korea, the incidence of MDS and AML are comparable across these regions. Comparison of the molecular alterations in AML, MDS, and CMML across Caucasian and East Asian populations as well as the frequencies of these alterations suggested that the cytogenetic and mutational landscape is generally similar across these ethnicities. Literature research indicated that AZA shows comparable efficacy (response rate and hematologic improvement) in pts from Japan and South Korea. Preliminary PEV PK data from 18 pts (including 8 from Japan, 7 from Taiwan, and 3 from South Korea in Study P1012) indicated similar PEV PK profiles in East Asian (37%) and Western pts (geometric mean dose-normalized AUC48h of 1167 [CV of 37%] and 1065 h*ng/mL [CV of 32%], respectively). In addition, systemic PEV exposures were consistent across the major East Asian races (ie, Japanese, Korean, Chinese). The safety profile of PEV alone or in combination with AZA in East Asian pts was generally comparable to that observed in Western pts. Based on the assumption that the treatment effects in Japanese/East Asian pts are similar to those in the overall population, with a total of 30 East Asian pts, the estimated probabilities of achieving consistent efficacy outcomes (measured by event-free survival and overall survival) between East Asian pts and the overall 450 pts in the global pivotal trial P3001 are >80%.
Conclusion
Intrinsic and extrinsic factors relevant to disease (HR MDS, CMML, and low-blast AML) and PEV were inferred to be similar across the planned countries of enrollment in the pooled East Asian region (Japan, South Korea) and between East Asian and Western regions. Clinical efficacy and safety data from the P3001 phase 3 study are therefore applicable to inform benefit-risk assessment for the East Asian population and are additionally justified to be pooled across pts enrolled for purposes of assessing consistency in the benefit-risk profile in East Asian populations.
Session topic: 10. Myelodysplastic syndromes – Clinical
Keyword(s): Acute Myeloid Leukemia, Myelodysplasia