We will conduct Phase I clinical trials of new anticancer agents or combinations of anticancer agents for the purposes of characterizing drug toxicity, determining the maximum tolerated dose, performing pharmacogenetic analysis, evaluating the pharmacokinetics, and relating clinical endpoints to the derived pharmacokinetic parameters, pharmacogenetics, and/or relevant biologic endpoints. A major focus of this application is the study agents that interact with novel targets such as signal transduction pathways, cell cycle regulation checkpoints, DNA repair pathways and apoptosis regulators, either alone or in combination with standard chemotherapy. The endpoints for the evaluation of such treatments will be clinical effect (toxicity and antineoplastic response) as well as alterations in biochemical pathways affected in preclinical model systems.
The specific aims of these studies are: to determine as efficiently as is compatible with patient safety the appropriate dose of new anticancer agents selected by the National Cancer Institute for evaluation of therapeutic activity in subsequent Phase II trials;to identify clinical, pharmacokinetic or other laboratory parameters that may predict toxicity;to determine whether functional polymorphisms of drug metabolizing or other enzymes associated with drug response alter pharmacokinetics, toxicity and/or activity of agents being studied;and to evaluate biological endpoints that may be used as surrogate markers of drug effect. Studies of drug combinations will be designed based on preclinical data identifying the appropriate schedule and exposure duration of the agents in vitro. Studies of novel modulating agents will be constructed to monitor and evaluate the intended modulation. Each new agent will be evaluated using a standard modified Fibonacci dose escalation scheme or novel dose-escalation methods as appropriate. Studies will be designed to incorporate the appropriate pharmacokinetic and pharmacogenetic analysis, drug analysis, and pharmacodynamic assessments. Pharmacokinetic/pharmacodynamic modeling of the data will be performed in those studies in which it is appropriate. By performing Phase I studies in this fashion, we will facilitate translation of novel preclinical observations into treatments that can be assessed for efficacy in Phase II and Phase III trials.

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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Mayo Clinic, Rochester
United States
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Goetz, Matthew P; Suman, Vera J; Reid, Joel M et al. (2017) First-in-Human Phase I Study of the Tamoxifen Metabolite Z-Endoxifen in Women With Endocrine-Refractory Metastatic Breast Cancer. J Clin Oncol 35:3391-3400
Pratz, Keith W; Rudek, Michelle A; Gojo, Ivana et al. (2017) A Phase I Study of Topotecan, Carboplatin and the PARP Inhibitor Veliparib in Acute Leukemias, Aggressive Myeloproliferative Neoplasms, and Chronic Myelomonocytic Leukemia. Clin Cancer Res 23:899-907
Hubbard, Joleen M; Kim, George; Borad, Mitesh J et al. (2016) Phase I trial of FOLFIRI in combination with sorafenib and bevacizumab in patients with advanced gastrointestinal malignancies. Invest New Drugs 34:96-103
Deming, Dustin A; Ninan, Jacob; Bailey, Howard H et al. (2014) A Phase I study of intermittently dosed vorinostat in combination with bortezomib in patients with advanced solid tumors. Invest New Drugs 32:323-9
Schelman, William R; Traynor, Anne M; Holen, Kyle D et al. (2013) A phase I study of vorinostat in combination with bortezomib in patients with advanced malignancies. Invest New Drugs 31:1539-46
Schenk, Erin; Hendrickson, Andrea E Wahner; Northfelt, Donald et al. (2013) Phase I study of tanespimycin in combination with bortezomib in patients with advanced solid malignancies. Invest New Drugs 31:1251-6
Kumar, Shaji K; Jett, James; Marks, Randolph et al. (2013) Phase 1 study of sorafenib in combination with bortezomib in patients with advanced malignancies. Invest New Drugs 31:1201-6
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
Goetz, Matthew P; McKean, Heidi A; Reid, Joel M et al. (2013) UGT1A1 genotype-guided phase I study of irinotecan, oxaliplatin, and capecitabine. Invest New Drugs 31:1559-67
Holkova, Beata; Supko, Jeffrey G; Ames, Matthew M et al. (2013) A phase I trial of vorinostat and alvocidib in patients with relapsed, refractory, or poor prognosis acute leukemia, or refractory anemia with excess blasts-2. Clin Cancer Res 19:1873-83

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