PHY906 is a traditional Chinese herbal medicine that has been used in the Orient for nearly 2000 years to treat diarrhea and nausea/vomiting. Our research group has developed a novel cGMP formulation of PHY906 that has been shown to be free of heavy metals and any other contaminants. We have characterized the preclinical activity of PHY906 as a modulator of cytotoxicity of anticancer agents and a cytoprotective agent of chemotherapy. An extensive series of pre-clinical in vivo studies using mouse xenograft models have shown that this herbal medicine can enhance the antitumor activity of a broad range of anticancer agents, including the topo I inhibitor irinotecan, and reduce toxicity. Preliminary results from an initial phase l/lla clinical study with PHY906 in combination with IFL chemotherapy in the front-line treatment of advanced CRC patients showed that PHY906 was able to effectively reduce the Gl toxicities of diarrhea and nausea/vomiting as well as overall fatigue. These observations suggested that PHY906 can reduce the toxicities associated with irinotecan-based chemotherapy. However, this initial pilot study was unable to determine the potential effect of PHY906 on the clinical efficacy of irinotecan chemotherapy. Our hypothesis is that PHY906 will be able to enhance the safety profile associated with irinotecan chemotherapy and maintain, if not improve, the clinical activity associated with this anticancer agent. To directly address this hypothesis, we plan to conduct a randomized, double-blind, placebo-controlled phase II clinical trial to investigate the effects ofthe Chinese herbal medicine PHY906 on the toxicity, quality of life, and clinical efficacy of irinotecan monotherapy in the treatment of patients with advanced CRC in the second-line setting. Patients will be randomized to receive the control arm of irinotecan plus placebo or to the experimental arm of irinotecan plus PHY906. As part of this clinical study, 3 specific aims are proposed:
Aim 1 will determine the effect of PHY906 on the safety profile of irinotecan monotherapy with a focus on Gl toxicity, in the form of diarrhea and nausea/vomiting, as well as myelosuppression and fatigue.
Aim 2 will investigate the effect of PHY906 on overall quality of life associated with irinotecan monotherapy using well-established and validated patient-reported assessment tools.
Aim 3 will investigate the effect of PHY906 on the clinical efficacy of irinotecan monotherapy with respect to overall response rates, progression-free survival, and overall survival.

Public Health Relevance

The findings from this Project may serve as a new paradigm for developing Chinese herbal medicines in combination with standard cancer chemotherapy. Such a treatment approach could then be applied for the treatment of other human cancers. These studies may also provide the scientific basis for developing other herbal medicines in cancer treatment as well as other human diseases.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Program Projects (P01)
Project #
5P01CA154295-04
Application #
8727477
Study Section
Special Emphasis Panel (ZCA1-GRB-S)
Project Start
Project End
Budget Start
2014-09-01
Budget End
2015-08-31
Support Year
4
Fiscal Year
2014
Total Cost
$491,312
Indirect Cost
$257,289
Name
Yale University
Department
Type
DUNS #
043207562
City
New Haven
State
CT
Country
United States
Zip Code
06520
Chen, Mengjie; Ren, Zhao; Zhao, Hongyu et al. (2016) Asymptotically Normal and Efficient Estimation of Covariate-Adjusted Gaussian Graphical Model. J Am Stat Assoc 111:394-406
Li, Cong; Yang, Can; Hather, Greg et al. (2016) Efficient Drug-Pathway Association Analysis via Integrative Penalized Matrix Decomposition. IEEE/ACM Trans Comput Biol Bioinform 13:531-40
Lin, Zhixiang; Li, Mingfeng; Sestan, Nenad et al. (2016) A Markov random field-based approach for joint estimation of differentially expressed genes in mouse transcriptome data. Stat Appl Genet Mol Biol 15:139-50
Zhu, Ruoqing; Zhao, Qing; Zhao, Hongyu et al. (2016) Integrating multidimensional omics data for cancer outcome. Biostatistics 17:605-18
Wang, Tao; Chen, Mengjie; Zhao, Hongyu (2016) Estimating DNA methylation levels by joint modeling of multiple methylation profiles from microarray data. Biometrics 72:354-63
Ryslik, Gregory A; Cheng, Yuwei; Modis, Yorgo et al. (2016) Leveraging protein quaternary structure to identify oncogenic driver mutations. BMC Bioinformatics 17:137
Huang, Xiu; Stern, David F; Zhao, Hongyu (2016) Transcriptional Profiles from Paired Normal Samples Offer Complementary Information on Cancer Patient Survival--Evidence from TCGA Pan-Cancer Data. Sci Rep 6:20567
Hu, Yiming; Zhao, Hongyu (2016) CCor: A whole genome network-based similarity measure between two genes. Biometrics 72:1216-1225
Wang, Ying; Lam, Wing; Chen, Shao-Ru et al. (2016) Tylophorine Analog DCB-3503 Inhibited Cyclin D1 Translation through Allosteric Regulation of Heat Shock Cognate Protein 70. Sci Rep 6:32832
Tsou, Lun K; Lara-Tejero, María; RoseFigura, Jordan et al. (2016) Antibacterial Flavonoids from Medicinal Plants Covalently Inactivate Type III Protein Secretion Substrates. J Am Chem Soc 138:2209-18

Showing the most recent 10 out of 40 publications