The premise behind this grant application is that impeccable characterization and understanding of a systemically administered new antineoplastic agent's pharmacology and effect on molecular targets in cancer should allow better clinical utilization of that agent. Determination of clinical toxicities and maximum tolerated dose (MTD) of an agent is no longer sufficient. Ideally, early clinical trials of an investigational agent should define pharmacokinetic (PK) disposition and metabolism, with correlation to pharmacodynamic (PD) manifestations at molecular, cellular, and clinical levels. With this abiding philosophy and hypothesis, performance of scientifically directed phase I trials of promising novel anti-cancer agents available through the National Cancer Institute is warranted. Integrating information regarding the mechanism of action and effect on molecular targets with development of biomarkers in phase I trials is the strategy that will be pursued with the following objectives to : define the toxicities of new antineoplastic agents in patients with advanced cancer;re-define (as necessary)the toxicities and PK of existing anticancer agents administered in combination with molecularly targeted agents, colony stimulating factors and other toxicity-ameliorating agents that may facilitate the exploration of more effective doses and schedules;provide information on the absorption, distribution, metabolism, and elimination of antitumor agents;define treatment regimens for use in phase II trials;establish, based on clinical and pharmacologic characteristics, appropriate phase II doses in special patient populations (e.g., patients with impaired organ function;heavily pretreated patients or geriatric patient populations), explore PK and PD differences based on sex, race, or ethnic group;obtain preliminary information on PK/PD correlations that can then be extended in phase II trials;incorporate basic laboratory and correlative science studies, when possible and appropriate, to enhance the understanding of the biochemical and/or biological mechanisms of drug actions;study the PK and the PD impact of drugs on specific metabolic pathways and molecular targets using non-invasive techniques such as magnetic resonance spectroscopy and nuclear imaging with radio-labeled drugs;and integrate pharmacogenomic studies to characterize differences in relevant drug metabolizing enzymes and drug targets related to toxicity and efficacy.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Research Project--Cooperative Agreements (U01)
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Special Emphasis Panel (ZCA1-SRRB-K (O1))
Program Officer
Ivy, S Percy
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University of Pittsburgh
Internal Medicine/Medicine
Schools of Medicine
United States
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Bodugam, Mahipal; Javed, Salim; Ganguly, Arghya et al. (2016) A Pot-Economical Approach to the Total Synthesis of Sch-725674. Org Lett 18:516-9
Villaruz, Liza C; Jones, Helen; Dacic, Sanja et al. (2016) ATM protein is deficient in over 40% of lung adenocarcinomas. Oncotarget :
Beumer, Jan H; Ding, Fei; Tawbi, Hussein et al. (2016) Effect of Renal Dysfunction on Toxicity in Three Decades of Cancer Therapy Evaluation Program-Sponsored Single-Agent Phase I Studies. J Clin Oncol 34:110-6
Lee, Dae-Hee; Zhang, Ying; Kassam, Amin B et al. (2015) Combined PDGFR and HDAC Inhibition Overcomes PTEN Disruption in Chordoma. PLoS One 10:e0134426
Newman, Edward M; Morgan, Robert J; Kummar, Shivaani et al. (2015) A phase I, pharmacokinetic, and pharmacodynamic evaluation of the DNA methyltransferase inhibitor 5-fluoro-2'-deoxycytidine, administered with tetrahydrouridine. Cancer Chemother Pharmacol 75:537-46
Appleman, Leonard J; Balasubramaniam, Sanjeeve; Parise, Robert A et al. (2015) A phase i study of DMS612, a novel bifunctional alkylating agent. Clin Cancer Res 21:721-9
Parise, Robert A; Eiseman, Julie L; Clausen, Dana M et al. (2015) Characterization of the metabolism of benzaldehyde dimethane sulfonate (NSC 281612, DMS612). Cancer Chemother Pharmacol 76:537-46
Parikh, Rahul A; Wang, Peng; Beumer, Jan H et al. (2014) The potential roles of hepatocyte growth factor (HGF)-MET pathway inhibitors in cancer treatment. Onco Targets Ther 7:969-83
Tawbi, Hussein (2014) Matching wits with melanoma brain metastases: from biology to therapeutics. Clin Cancer Res 20:5346-8
Owonikoko, Taofeek K; Zhang, Guojing; Deng, Xingming et al. (2014) Poly (ADP) ribose polymerase enzyme inhibitor, veliparib, potentiates chemotherapy and radiation in vitro and in vivo in small cell lung cancer. Cancer Med 3:1579-94

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