The specific goals of the grant are: a. To define the acute toxicities of new anticancer agents in patients with advanced cancer. b. To re-define the acute toxicities and pharmacokinetics of existing anticancer agents administered in combination with colony stimulating factors and other toxicity-ameliorating agents which may facilitate the exploration of more effective doses and schedules. c. To provide information on the pharmacologic characteristics (absorption, distribution, metabolism, and elimination) of selected antitumor agents. d. To define treatment regimens for evaluation of antitumor activity in Phase II trials. e. Based on pharmacologic characteristics, to establish appropriate Phase II doses in special patient populations, such as those with impaired end- organ function or with heavy pretreatment, geriatric populations, and to explore pharmacokinetic and pharmacodynamic differences based on gender, race or ethnic group. f. To obtain preliminary information on pharmacokinetic/pharmacodynamic correlations with can then be extended in Phase II trials. g. To incorporate ancillary basic laboratory studies, when possible and appropriate, to enhance our understanding of the biochemical and/or biological mechanisms of drug actions. The agents to be studied will include the following: a. Cytotoxic chemotherapeutic agents identified by the NCIs drug screening program. b. Cytotoxic agents with novel mechanisms, including antiangiogenesis agents, differentiating agents, apoptosis-inducing agents, anti-sense oligonucleotides and related gene-specific therapeutic agents, and targeted cytoxic agents. C. Existing chemotherapeutic agents which, when administered with colony stimulating factors or other agents to ameliorate dose-limiting toxicities, can be given in doses substantially higher than those previously tested. d. Agents developed by the pharmaceutical industry and provided to the NCI for collaborative development. This grant shall accrue at least 25-50 patients per year to at least three active phase I trials per year for five years. Pharmacokinetics and/or correlative lab studies shall be a standard feature of these studies. Pharmacokinetics will be assessed in an ongoing manner in proximity to treatment rather than in a batched manner to facilitate incorporation of pharmacokinetic data in dosing decision-making. Some phase I studies of combination and/or modulation studies may not require intensive pharmacokinetic data collection and this, as well as the credit to be assigned, will be determined at the time of the Letter of intent (LOI) review or protocol review by program staff.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project--Cooperative Agreements (U01)
Project #
1U01CA069854-01
Application #
2113827
Study Section
Special Emphasis Panel (NSS)
Project Start
1995-05-15
Project End
1998-02-28
Budget Start
1995-05-15
Budget End
1996-02-29
Support Year
1
Fiscal Year
1995
Total Cost
Indirect Cost
Name
University of Maryland Baltimore
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
003255213
City
Baltimore
State
MD
Country
United States
Zip Code
21201
Zeidan, Amer M; Ricklis, Rebecca M; Carraway, Hetty E et al. (2012) Phase 1 dose-escalation trial of clofarabine followed by escalating dose of fractionated cyclophosphamide in adults with relapsed or refractory acute leukaemias. Br J Haematol 158:198-207
Karp, Judith E; Smith, B Douglas; Resar, Linda S et al. (2011) Phase 1 and pharmacokinetic study of bolus-infusion flavopiridol followed by cytosine arabinoside and mitoxantrone for acute leukemias. Blood 117:3302-10
Fathi, Amir T; Grant, Steven; Karp, Judith E (2010) Exploiting cellular pathways to develop new treatment strategies for AML. Cancer Treat Rev 36:142-50
Karp, Judith E; Blackford, Amanda; Smith, B Douglas et al. (2010) Clinical activity of sequential flavopiridol, cytosine arabinoside, and mitoxantrone for adults with newly diagnosed, poor-risk acute myelogenous leukemia. Leuk Res 34:877-82
Fathi, Amir T; Karp, Judith E (2009) New agents in acute myeloid leukemia: beyond cytarabine and anthracyclines. Curr Oncol Rep 11:346-52
Karp, Judith E; Smith, B Douglas; Gojo, Ivana et al. (2008) Phase II trial of tipifarnib as maintenance therapy in first complete remission in adults with acute myelogenous leukemia and poor-risk features. Clin Cancer Res 14:3077-82
Gojo, Ivana; Jiemjit, Anchalee; Trepel, Jane B et al. (2007) Phase 1 and pharmacologic study of MS-275, a histone deacetylase inhibitor, in adults with refractory and relapsed acute leukemias. Blood 109:2781-90
Lancet, Jeffrey E; Gojo, Ivana; Gotlib, Jason et al. (2007) A phase 2 study of the farnesyltransferase inhibitor tipifarnib in poor-risk and elderly patients with previously untreated acute myelogenous leukemia. Blood 109:1387-94
Badros, Ashraf Z; Goloubeva, Olga; Rapoport, Aaron P et al. (2005) Phase II study of G3139, a Bcl-2 antisense oligonucleotide, in combination with dexamethasone and thalidomide in relapsed multiple myeloma patients. J Clin Oncol 23:4089-99
Bauer, Kenneth S; Karp, Judith E; Garimella, Tushar S et al. (2005) A phase I and pharmacologic study of idarubicin, cytarabine, etoposide, and the multidrug resistance protein (MDR1/Pgp) inhibitor PSC-833 in patients with refractory leukemia. Leuk Res 29:263-71

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