Phase I pharmacodynamic study of time and sequence dependency of hydroxyurea in combination with gemcitabine: A California cancer consortium trial

Yun Yen, Warren Chow, Lucille Leong, Kim Margolin, Robert Morgan, James Raschko, Stephen Shibata, George Somlo, Przemyslaw Twardowski, Paul Frankel, Jeff Longmate, Timothy Synold, Edward M. Newman, Heinz Josef Lenz, David Gandara, James H. Doroshow

Research output: Contribution to journalArticle

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Abstract

Preclinical studies in our laboratory have demonstrated that prior exposure to hydroxyurea increases the percentage of cells in S phase, enhancing the cytotoxicity of subsequent gemcitabine treatment in human oropharyngeal KB cells. To evaluate the clinical implications of this time- and sequence-dependent potentiation, we performed a phase I trial of hydroxyurea given over 24 h followed by a 30-min infusion of gemcitabine in weeks 1 and 2 of a 3-week cycle. The dose of hydroxyurea was fixed at 500 mg orally every 6 h for four doses starting 24 h before each dose of gemcitabine. The initial dose level of gemcitabine was 250 mg/m2 on days 2 and 9, and this was escalated stepwise to 1000 mg/m2 on days 2 and 9. Gemcitabine pharmacokinetics were determined on days 2 and 9 of the first cycle. Of 27 patients enrolled (12 female, 15 male), 24 were evaluable for response and 23 were evaluable for toxicity. Their median age was 56 years (range 27-76 years). Tumor types included lung, head and neck, pancreas, breast, colon, prostate, stomach, ovary, esophagus, germ cell, thyroid, gallbladder, and unknown primary. A total of 80 cycles of treatment were completed. One patient (unknown primary) had an objective partial response lasting 21 months, and 12 patients had stable disease. All observed dose-limiting toxicities were related to myelosuppression. The gemcitabine maximum tolerated dose was established at 750 mg/m2 on days 2 and 9. Hydroxyurea had no effect on the plasma pharmacokinetics of gemcitabine. These results suggest that hydroxyurea followed by gemcitabine can be safely administered and has activity on this schedule. We are presently developing a phase II trial of this regimen for patients with platinum-resistant head and neck cancer.

Original languageEnglish
Pages (from-to)353-359
Number of pages7
JournalCancer Chemotherapy and Pharmacology
Volume50
Issue number5
DOIs
Publication statusPublished - Dec 21 2002
Externally publishedYes

Fingerprint

gemcitabine
Pharmacodynamics
Hydroxyurea
Neoplasms
Pharmacokinetics
Toxicity
KB Cells
Maximum Tolerated Dose
Cytotoxicity
Head and Neck Neoplasms
Gallbladder
Platinum
S Phase
Germ Cells
Esophagus
Tumors
Prostate
Pancreas
Ovary
Stomach

Keywords

  • Drug sequence
  • Gemcitabine
  • Hydroxyurea
  • Ribonucleotide reductase

ASJC Scopus subject areas

  • Oncology
  • Toxicology
  • Pharmacology
  • Cancer Research
  • Pharmacology (medical)

Cite this

Phase I pharmacodynamic study of time and sequence dependency of hydroxyurea in combination with gemcitabine : A California cancer consortium trial. / Yen, Yun; Chow, Warren; Leong, Lucille; Margolin, Kim; Morgan, Robert; Raschko, James; Shibata, Stephen; Somlo, George; Twardowski, Przemyslaw; Frankel, Paul; Longmate, Jeff; Synold, Timothy; Newman, Edward M.; Lenz, Heinz Josef; Gandara, David; Doroshow, James H.

In: Cancer Chemotherapy and Pharmacology, Vol. 50, No. 5, 21.12.2002, p. 353-359.

Research output: Contribution to journalArticle

Yen, Y, Chow, W, Leong, L, Margolin, K, Morgan, R, Raschko, J, Shibata, S, Somlo, G, Twardowski, P, Frankel, P, Longmate, J, Synold, T, Newman, EM, Lenz, HJ, Gandara, D & Doroshow, JH 2002, 'Phase I pharmacodynamic study of time and sequence dependency of hydroxyurea in combination with gemcitabine: A California cancer consortium trial', Cancer Chemotherapy and Pharmacology, vol. 50, no. 5, pp. 353-359. https://doi.org/10.1007/s00280-002-0492-9
Yen, Yun ; Chow, Warren ; Leong, Lucille ; Margolin, Kim ; Morgan, Robert ; Raschko, James ; Shibata, Stephen ; Somlo, George ; Twardowski, Przemyslaw ; Frankel, Paul ; Longmate, Jeff ; Synold, Timothy ; Newman, Edward M. ; Lenz, Heinz Josef ; Gandara, David ; Doroshow, James H. / Phase I pharmacodynamic study of time and sequence dependency of hydroxyurea in combination with gemcitabine : A California cancer consortium trial. In: Cancer Chemotherapy and Pharmacology. 2002 ; Vol. 50, No. 5. pp. 353-359.
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