) The overall objectives of this UO1 application are to provide support for both phase I trials of new anticancer a g ents and for pharmacokinetics, pharmacodynamic and other laboratory correlative studies in cancer patients receiving these agents. These studies will be performed by the Harvard/Boston phase I Oncology Group consisting of investigators at the Dana-Faber Partners Cancer Care (Dana-Farber Cancer Institute, Brigham and Women's Hospital, Massachusetts General Hospital), Beth I s rael-Deaconess Medical Center Boston Medical Center, and Children's Hospital. The specific goals are the following: 1) To define the toxicities of new anti-c a n c er agents in patients with advanced cancer; 2) to define the pharmacokinetics characteristics (absorption, distribution, metabolism and elimination) and pharmacodynamics (effects at the biochemical and molecular levels)of these agents; and 3) to determine a treatment regimen suitable for evaluation of anti-tumor activity in phase II trials. The scope of the program will include phase I and laboratory studies of 1) investigational new cytotoxic drugs; 2) differentiating agents; and 3) anti-angiogenesis agents. In addition to phamacokint analyses, laboratory studies, depending on the agent, will focus on regulation of specific gene expression, differentiation and inhibition of angiogenesis. Since the agents to be studied are at this point, we have selected as examples the following: 1) KRN5500 (spicamycin), an inducer of differentiation; and angiostatin, a new inhibitor of angiogenesis. Phase I pharmacokinetics trials of KRN5500 and a n g i o s tatin, as well as the appropriate laboratory correlates of p h a r macodynamics or biologic response, are included as examples of investigator-originated research to be conduct group.
The specific aims are: 1) to conduct a Phase I, pharmacokinetic and pharmacodynamic trial of the differentiating agent KRN5500; and 2) to conduct a Phase 1, pharmacokinetic and pharmacodynamic trial of the angiogenesis inhibitor angiostatin.
|LoRusso, Patricia M; Li, Jing; Burger, Angelika et al. (2016) Phase I Safety, Pharmacokinetic, and Pharmacodynamic Study of the Poly(ADP-ribose) Polymerase (PARP) Inhibitor Veliparib (ABT-888) in Combination with Irinotecan in Patients with Advanced Solid Tumors. Clin Cancer Res 22:3227-37|
|Liu, Joyce F; Barry, William T; Birrer, Michael et al. (2014) Combination cediranib and olaparib versus olaparib alone for women with recurrent platinum-sensitive ovarian cancer: a randomised phase 2 study. Lancet Oncol 15:1207-14|
|Shibata, Stephen I; Chung, Vincent; Synold, Timothy W et al. (2013) Phase I study of pazopanib in patients with advanced solid tumors and hepatic dysfunction: a National Cancer Institute Organ Dysfunction Working Group study. Clin Cancer Res 19:3631-9|
|Abrams, Jeffrey S; Mooney, Margaret M; Zwiebel, James A et al. (2013) Implementation of timeline reforms speeds initiation of National Cancer Institute-sponsored trials. J Natl Cancer Inst 105:954-9|
|Liu, Joyce F; Tolaney, Sara M; Birrer, Michael et al. (2013) A Phase 1 trial of the poly(ADP-ribose) polymerase inhibitor olaparib (AZD2281) in combination with the anti-angiogenic cediranib (AZD2171) in recurrent epithelial ovarian or triple-negative breast cancer. Eur J Cancer 49:2972-8|
|Lu-Emerson, Christine; Snuderl, Matija; Kirkpatrick, Nathaniel D et al. (2013) Increase in tumor-associated macrophages after antiangiogenic therapy is associated with poor survival among patients with recurrent glioblastoma. Neuro Oncol 15:1079-87|
|Haigentz Jr, Missak; Kim, Mimi; Sarta, Catherine et al. (2012) Phase II trial of the histone deacetylase inhibitor romidepsin in patients with recurrent/metastatic head and neck cancer. Oral Oncol 48:1281-8|
|Raut, Chandrajit P; Boucher, Yves; Duda, Dan G et al. (2012) Effects of sorafenib on intra-tumoral interstitial fluid pressure and circulating biomarkers in patients with refractory sarcomas (NCI protocol 6948). PLoS One 7:e26331|
|Eichler, April F; Chung, Euiheon; Kodack, David P et al. (2011) The biology of brain metastases-translation to new therapies. Nat Rev Clin Oncol 8:344-56|
|Cleary, James M; Shapiro, Geoffrey I (2010) Development of phosphoinositide-3 kinase pathway inhibitors for advanced cancer. Curr Oncol Rep 12:87-94|
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