The overall objective of this U01 application from the Dana-Farber/Harvard Cancer Center (DF/HCC) is to provide clinical and scientific experience and patient resources to perform Phase I single agent clinical trials* Phase I agent combination clinical trials, limited Phase II clinical trials, and pilot clinical trials of novel anti- cancer agents. These studies will be performed by the DF/HCC Phase I Oncology Group consisting of investigators at the participating Dana-Farber Cancer Institute (DFCI), Brigham and Women's Hospital (BWH), Massachusetts General Hospital (MGH) and the Beth Israel Deaconess Medical Center (BIDMC) sites. The DF/HCC Phase I Oncology Group has interacted over the past 15 years (1992-2007) in the conduct of more than 70 Phase I, l-ll pharmacokinetic and pharmacodynamic clinical trials of investigational new cytotoxic agents, angiogenesis inhibitors, signal transduction/cell cycle inhibitors, differentiating agents and anti-cancer vaccines. Trials performed over the past 4 years (2003-2006, prior funding period) include 10 agents from the NCI Clinical Trials Evaluation Program (CTEP). The DF/HCC Phase I Oncology Group has accrued 219 patients to the 10 CTEP trials during 2003-2006 with an average accrual of 55 patients annually. These trials have been integrated with pharmacokinetic, biochemical, pathological, immunological, molecular and imaging studies that correlate effects of the agents on their targets.
The Specific Aims of the DF/HCC application are 1) To perform Phase I, limited Phase II and pilot clinical trials of novel agents in the NCI CTEP IND portfolio that target relevant cancer cell signaling pathways involved in the regulation of cell survival, proliferation, apoptosis, differentiation and angiogenesis;2) To assess pharmacokinetics of these agents when administered alone or in combination and establish relationships between dose, schedule, exposure and effect;3) To perform these trials with novel designs where appropriate, including accelerated titration and other advanced design schemes;4) To establish safe and biologically active treatment schedules for patients with cancer, including those with hepatic and/or renal dysfunction;5) To obtain mechanistic proof-of-principle data for new agents directed at novel molecular targets;and 6) To evaluate translational endpoints of expression and/or activity of molecular targets and downstream effectors that are regulated by these agents. The importance of this work to the public health is realized by the need for more and better treatment options for the substantial number of cancer patients who, because of disease unresponsive to existing treatments, become candidates for new investigational agents. The research proposed in this U01 agreement is focused on accelerating access of these cancer patients to new treatment strategies.
|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|
|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|
|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|
|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|
Showing the most recent 10 out of 20 publications