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Phase i trials in melanoma: A framework to translate preclinical findings to the clinic

Eunjung Kim, Vito W. Rebecca, Keiran S.M. Smalley, Alexander R.A. Anderson
doi: https://doi.org/10.1101/015925
Eunjung Kim
1 Integrated Mathematical Oncology Department, Moffitt Cancer Center and Research Institute, Tampa, Florida, USA
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Vito W. Rebecca
2 The Department of Tumor Biology, Moffitt Cancer Center and Research Institute, Tampa, Florida, USA
3 Current address: Department of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA
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Keiran S.M. Smalley
2 The Department of Tumor Biology, Moffitt Cancer Center and Research Institute, Tampa, Florida, USA
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Alexander R.A. Anderson
1 Integrated Mathematical Oncology Department, Moffitt Cancer Center and Research Institute, Tampa, Florida, USA
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Abstract

Abstract We present a, mathematical model driven, framework to implement virtual or imaginary clinical trials (phase i trials) that can be used to bridge the gap between preclinical studies and the clinic. The trial implementation process includes the development of an experimentally validated mathematical model, generation of a cohort of heterogeneous virtual patients, an assessment of stratification factors, and optimization of treatment strategy. We show the detailed process through application to melanoma treatment, using a combination therapy of chemotherapy and an AKT inhibitor, which was recently tested in a phase 1 clinical trial. We developed a mathematical model, composed of ordinary differential equations, based on experimental data showing that such therapies differentially induce autophagy in melanoma cells. Model parameters were estimated using an optimization algorithm that minimizes differences between predicted cell populations and experimentally measured cell numbers. The calibrated model was validated by comparing predicted cell populations with experimentally measured melanoma cell populations in twelve different treatment scheduling conditions. By using this validated model as the foundation for a genetic algorithm, we generated a cohort of virtual patients that mimics the heterogeneous combination therapy responses observed in a companion clinical trial. Sensitivity analysis of this cohort defined parameters that discriminated virtual patients having more favorable versus less favorable outcomes. Finally, the model predicts optimal therapeutic approaches across all virtual patients.

One Sentence Summary We propose a computational framework to implement phase i trials (virtual/imaginary yet informed clinical trials) in cancer, using an experimentally calibrated mathematical model of melanoma combination therapy, that can readily capture observed heterogeneous clinical outcomes and be used to optimize future clinical trial design.

Copyright 
The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC-ND 4.0 International license.
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Posted March 26, 2015.
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Phase i trials in melanoma: A framework to translate preclinical findings to the clinic
Eunjung Kim, Vito W. Rebecca, Keiran S.M. Smalley, Alexander R.A. Anderson
bioRxiv 015925; doi: https://doi.org/10.1101/015925
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Phase i trials in melanoma: A framework to translate preclinical findings to the clinic
Eunjung Kim, Vito W. Rebecca, Keiran S.M. Smalley, Alexander R.A. Anderson
bioRxiv 015925; doi: https://doi.org/10.1101/015925

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