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Translational research and application of basic biology to clinical trial development in GI cancers.

ABSTRACT: Cancers of the gastrointestinal tract have limited available treatments and are often associated with a poor prognosis. Clinical trials and translational work associated with these trials provide the opportunity to increase understanding of the mechanisms of sensitivity and resistance to cytotoxic chemotherapy and targeted therapy in these diseases. In this review we discuss the rationale for intensive translational work within the context of academic clinical trials and the successes and challenges which have been associated with translational work at our institution over the past number of years. We reflect on tissue, plasma and radiological biomarker work including a novel patient derived organoid programme and discuss the iterative application of previous results to next generation trial design.

SUBMITTER: Smyth E

PROVIDER: S-EPMC5985276 | biostudies-literature | 2018 May

REPOSITORIES: biostudies-literature

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Translational research and application of basic biology to clinical trial development in GI cancers.

Smyth Elizabeth E Khan Khurum K Valeri Nicola N

Annals of translational medicine 20180501 9

Cancers of the gastrointestinal tract have limited available treatments and are often associated with a poor prognosis. Clinical trials and translational work associated with these trials provide the opportunity to increase understanding of the mechanisms of sensitivity and resistance to cytotoxic chemotherapy and targeted therapy in these diseases. In this review we discuss the rationale for intensive translational work within the context of academic clinical trials and the successes and challe ...[more]

PMID: 29911112

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Project description: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. Study Highlights 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 investigational therapies for rare cancers and orphan diseases in Asia-inclusive multiregional clinical trials.

Dataset Information

Translational research and application of basic biology to clinical trial development in GI cancers.

Publications

Translational research and application of basic biology to clinical trial development in GI cancers.

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