Asia‐inclusive global development of pevonedistat: Clinical pharmacology and translational research enabling a phase 3 multiregional clinical trial

Abstract

The investigational NEDD8‐activating enzyme inhibitor pevonedistat is being evaluated in combination with azacitidine versus single‐agent azacitidine in patients with higher‐risk myelodysplastic syndrome (higher‐risk MDS), higher‐risk chronic myelomonocytic leukemia (higher‐risk CMML), or low‐blast acute myeloid leukemia (AML) in a Phase 3 trial PANTHER. To support Asia‐inclusive global development, we applied multiregional clinical trial (MRCT) principles of the International Conference on Harmonisation E17 guidelines by evaluating similarity in drug‐related and disease‐related intrinsic and extrinsic factors. A PubMed literature review (January 2000–November 2019) supported similarity in epidemiology of higher‐risk MDS, AML, and CMML in Western and East Asian populations. Furthermore, the treatment of MDS/AML was similar in both East Asian and Western regions, with the same dose of azacitidine being the standard of care. Median overall survival in MDS following azacitidine treatment was generally comparable across regions, and the types and frequencies of molecular alterations in AML and MDS were comparable. Dose‐escalation studies established the same maximum tolerated dose of pevonedistat in combination with azacitidine in Western and East Asian populations. Pevonedistat clearance was similar across races. Taken together, conservation of drug‐related and disease‐related intrinsic and extrinsic factors supported design of an Asia‐inclusive Phase 3 trial and a pooled East Asian region. A sample size of ~ 30 East Asian patients (of ~ 450 randomized) was estimated as needed to demonstrate consistency in efficacy relative to the global population. This analysis is presented as an exemplar to illustrate application of clinical pharmacology and translational science principles in designing Asia‐inclusive MRCTs. WHAT IS THE CURRENT KNOWLEDGE ON THE TOPIC? Azacitidine is the standard of care for myelodysplastic syndromes/low‐blast acute myeloid leukemia (AML) across Western and East Asian patients. The first‐in‐class small‐molecule inhibitor of NEDD8‐activating enzyme, pevonedistat, has been investigated as a single agent in multiple studies of hematologic and nonhematologic malignancies and in combination with azacitidine in elderly patients with untreated AML. WHAT QUESTION DID THIS STUDY ADDRESS? By applying clinical pharmacology and translational science and International Conference on Harmonisation E17 principles, this study designed an East Asian‐inclusive global pivotal Phase 3 trial of pevonedistat, taking into consideration drug‐related and disease‐related intrinsic and extrinsic factors. WHAT DOES THIS STUDY ADD TO OUR KNOWLEDGE? These analyses provide scientific rationale for Asia‐inclusive globalization of the pivotal, Phase 3 PANTHER trial and for pooling clinical data across the East Asian region for assessing consistency in efficacy. HOW MIGHT THIS CHANGE CLINICAL PHARMACOLOGY OR TRANSLATIONAL SCIENCE? We developed a framework to facilitate efficient global clinical development of inve...

Population pharmacokinetic and exposure‐response analyses from ALTA‐1L: Model‐based analyses supporting the brigatinib dose in ALK‐positive NSCLC

“…ALTA‐1L was a multiregional clinical trial, and the demonstration of consistent systemic brigatinib exposures in Asian and White races (Figure S5B) provides further evidence that brigatinib PK is not sensitive to ethnic factors 11 . Taken together with the lack of discernible exposure‐safety relationships observed in our analyses, these findings support an overall assessment of low ethnic sensitivity of brigatinib, of importance to informing scientifically guided Asia‐inclusive development and use 17,18 …”

“… 11 Taken together with the lack of discernible exposure‐safety relationships observed in our analyses, these findings support an overall assessment of low ethnic sensitivity of brigatinib, of importance to informing scientifically guided Asia‐inclusive development and use. 17 , 18 …”

“…11 Taken together with the lack of discernible exposure-safety relationships observed in our analyses, these findings support an overall assessment of low ethnic sensitivity of brigatinib, of importance to informing scientifically guided Asia-inclusive development and use. 17,18 Results of exposure-PFS analyses based on static exposure metrics suggested a pharmacologically inconsistent positive relationship between increasing brigatinib exposure and risk of disease progression or death. Similar results were observed when a static exposure metric (average trough concentration) was used in exposureefficacy analyses of another ALK inhibitor, ceritinib.…”

NEDDylated Cullin 3 mediates the adaptive response to topoisomerase 1 inhibitors

“…In agreement with these findings, we also show that inhibition of the NEDDylation pathway with the NEDD8 inhibitor, pevonedistat (MLN4924), completely abrogates the adaptive response to TOP1 inhibitors and significantly sensitizes cancer cells to these drugs. Pevonedistat is currently in clinical trials for the treatment of different tumor types (98)(99)(100), and our data strongly suggest that this drug can be used to increase tumor response to TOP1 inhibitors.…”

Pharmacometric modeling and machine learning analyses of prognostic and predictive factors in the JAVELIN Gastric 100 phase III trial of avelumab

“…Assessment of conservation of disease-related intrinsic and extrinsic factors is an important consideration when applying International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use guidelines E5 and E17 for ethnic sensitivity assessment to support Asia-inclusive clinical development strategies. [35][36][37][38][39] The results of our analyses indicate the lack of discernable differences in disease progression or outcomes between Asian and non-Asian populations and are valuable to inform the design of Asia-inclusive trials in GC in the postinduction setting.…”