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Genomic and epigenomic predictors of response to Guadecitabine in relapsed/refractory Acute Myelogenous Leukemia

ABSTRACT: Guadecitabine is a second generation DNA methylation inhibitor with improved pharmacokinetics and clinical activity in relapsed/refractory AML (rrAML). Here we report genome-wide DNA methylation profiles in pre-treatment samples from 116 rrAML patients treated at therapeutic doses of guadecitabine in a phase I/II study. Response rate to guadecitabine was 22 % (16CR, 42 12CRi/CRp). There were no strong mutation or methylation predictors of response. Gene expression defined a subset of patients (~20%) that had (i) high DNMT3B and low CDKN2B, CTCF and CDA expression, (ii) enrichment for KRAS/NRAS mutations, (iii) frequent CpG island hypermethylation (iv) low LINE1 hypomethylation after treatment and (v) resistance to guadecitabine in both phase I (response rate 0 % vs 33 %, p=0.07) and phase II components of the study (response rate 5 % vs. 30 %, p=0.02). Multivariate analysis identified peripheral blood blasts and hemoglobin as predictors of response and cytogenetics, gene expression, RAS mutations and hemoglobin as predictors of survival. Thus, a subset of patients (∿ 20%) with rrAML are unlikely to benefit from single agent guadecitabine. In the remaining 80%, guadecitabine is a viable option with a median survival of ∿ 8 months and a three year survival rate of over 20%.

ORGANISM(S): Homo sapiens

PROVIDER: GSE112838 | GEO | 2019/08/06

REPOSITORIES: GEO

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Project description:Claret2009 - Predicting phase III overall survival in colorectal cancer This model is described in the article: Model-based prediction of phase III overall survival in colorectal cancer on the basis of phase II tumor dynamics. Claret L, Girard P, Hoff PM, Van Cutsem E, Zuideveld KP, Jorga K, Fagerberg J, Bruno R. J. Clin. Oncol. 2009 Sep; 27(25): 4103-4108 Abstract: PURPOSE: We developed a drug-disease simulation model to predict antitumor response and overall survival in phase III studies from longitudinal tumor size data in phase II trials. METHODS: We developed a longitudinal exposure-response tumor-growth inhibition (TGI) model of drug effect (and resistance) using phase II data of capecitabine (n = 34) and historical phase III data of fluorouracil (FU; n = 252) in colorectal cancer (CRC); and we developed a parametric survival model that related change in tumor size and patient characteristics to survival time using historical phase III data (n = 245). The models were validated in simulation of antitumor response and survival in an independent phase III study (n = 1,000 replicates) of capecitabine versus FU in CRC. RESULTS: The TGI model provided a good fit of longitudinal tumor size data. A lognormal distribution best described the survival time, and baseline tumor size and change in tumor size from baseline at week 7 were predictors (P < .00001). Predicted change of tumor size and survival time distributions in the phase III study for both capecitabine and FU were consistent with observed values, for example, 431 days (90% prediction interval, 362 to 514 days) versus 401 days observed for survival in the capecitabine arm. A modest survival improvement of 39 days (90% prediction interval, -21 to 110 days) versus 35 days observed was predicted for capecitabine. CONCLUSION: The modeling framework successfully predicted survival in a phase III trial on the basis of capecitabine phase II data in CRC. It is a useful tool to support end-of-phase II decisions and design of phase III studies. This model is hosted on BioModels Database and identified by: MODEL1708310001. To cite BioModels Database, please use: BioModels Database: An enhanced, curated and annotated resource for published quantitative kinetic models. To the extent possible under law, all copyright and related or neighbouring rights to this encoded model have been dedicated to the public domain worldwide. Please refer to CC0 Public Domain Dedication for more information.

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Genomic and epigenomic predictors of response to Guadecitabine in relapsed/refractory Acute Myelogenous Leukemia

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