Phase I clinical and pharmacologic study of Eniluracil plus fluorouracil in patients with advanced cancer

Richard L. Schilsky, John Hohneker, Mark J. Ratain, Linda Janisch, Leslie Smetzer, Virgil Sol Lucas, Soo Peang Khor, Robert B Diasio, Daniel D. Von Hoff, Howard A. Burris

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Abstract

Purpose: To determine the highest dose of fluorouracil (5-FU) that could be safely administered with Eniluracil (776C85; Glaxo Wellcome Inc, Research Triangle Park, NC), an inactivator of dihydropyrimidine dehydrogenase (DPD), on a daily schedule for 5 days, and to define the toxicities of the combination and the pharmacokinetics of 5-FU when administered with 776C85. Patients and Methods: Patients with advanced solid tumors refractory to standard therapy were enrolled at two institutions. The study consisted of three periods designed to evaluate the safety, pharmacokinetics, and pharmacodynamics of 776C85 alone (period 1); the effects of 776C85 on the pharmacokinetics of 5-FU (period 2); and the maximum-tolerated dose (MTD) of 5-FU, with or without leucovorin, that could be safely administered with 776C85 (period 3). Cohorts of at least three patients each received oral 776C85 alone at doses of 3.7 mg/m2/d, 18.5 mg/m2/d and 0.74 mg/m2/d. After a 14-day washout period, each patient then received 776C85 daily for 3 days, with a single intravenous (IV) bolus dose of 5-FU 10 mg/m2 on day 2. After a second washout period, patients were treated with 776C85 daily for 7 days and 5-FU IV bolus on days 2 through 6. The starting dose of 5-FU 10 mg/m2/d was escalated until the MTD was determined. After determination of the MTD of 5- FU given with 776C85, oral leucovorin 50 mg/d on days 2 through 6 was added to determine the MTD of 5-FU with leucovorin in the presence of 776C85. Near the completion of the study, additional cohorts of patients were treated with 776C85 at 50 mg/d and oral 5-FU with or without leucovorin. Results: Sixty- five patients were enrolled onto the study and 60 were assessable for toxicity and response. Bone marrow suppression was the primary and dose- limiting toxicity of this regimen. Other toxicities included diarrhea, mucositis, anemia, anorexia, nausea, vomiting, and fatigue. 776C85 suppressed DPD activity in peripheral-blood mononuclear cells (PBMCs) by at least 90% for at least 24 hours at all dose levels tested. In the presence of 776C85, 5-FU half-life was prolonged, clearance was reduced, and the drug displayed linear pharmacokinetics. Recommended doses for further testing on a daily for 5-day schedule are 776C85 10 mg/d with IV 5-FU 25 mg/m2/d; 776C85 10 mg/d with IV 5-FU 20 mg/m2/d plus leucovorin 50 mg/d; 776C85 50 mg/d with 5-FU given orally at 15 mg/m2/d with leucovorin at 50 mg/d. Conclusion: 5-FU can be safely administered with 776C85; however, the MTDs are considerably lower than those conventionally used, caused, at least in part, by marked alterations in 5-FU plasma pharmocokinetics.

Original languageEnglish (US)
Pages (from-to)1450-1457
Number of pages8
JournalJournal of Clinical Oncology
Volume16
Issue number4
StatePublished - Apr 1998
Externally publishedYes

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Fluorouracil
Neoplasms
Leucovorin
Maximum Tolerated Dose
Pharmacokinetics
Dihydrouracil Dehydrogenase (NADP)
Clinical Studies
eniluracil
Appointments and Schedules
Mucositis
Anorexia
Nausea
Vomiting
Fatigue
Half-Life
Anemia

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

Schilsky, R. L., Hohneker, J., Ratain, M. J., Janisch, L., Smetzer, L., Lucas, V. S., ... Burris, H. A. (1998). Phase I clinical and pharmacologic study of Eniluracil plus fluorouracil in patients with advanced cancer. Journal of Clinical Oncology, 16(4), 1450-1457.

Phase I clinical and pharmacologic study of Eniluracil plus fluorouracil in patients with advanced cancer. / Schilsky, Richard L.; Hohneker, John; Ratain, Mark J.; Janisch, Linda; Smetzer, Leslie; Lucas, Virgil Sol; Khor, Soo Peang; Diasio, Robert B; Von Hoff, Daniel D.; Burris, Howard A.

In: Journal of Clinical Oncology, Vol. 16, No. 4, 04.1998, p. 1450-1457.

Research output: Contribution to journalArticle

Schilsky, RL, Hohneker, J, Ratain, MJ, Janisch, L, Smetzer, L, Lucas, VS, Khor, SP, Diasio, RB, Von Hoff, DD & Burris, HA 1998, 'Phase I clinical and pharmacologic study of Eniluracil plus fluorouracil in patients with advanced cancer', Journal of Clinical Oncology, vol. 16, no. 4, pp. 1450-1457.
Schilsky RL, Hohneker J, Ratain MJ, Janisch L, Smetzer L, Lucas VS et al. Phase I clinical and pharmacologic study of Eniluracil plus fluorouracil in patients with advanced cancer. Journal of Clinical Oncology. 1998 Apr;16(4):1450-1457.
Schilsky, Richard L. ; Hohneker, John ; Ratain, Mark J. ; Janisch, Linda ; Smetzer, Leslie ; Lucas, Virgil Sol ; Khor, Soo Peang ; Diasio, Robert B ; Von Hoff, Daniel D. ; Burris, Howard A. / Phase I clinical and pharmacologic study of Eniluracil plus fluorouracil in patients with advanced cancer. In: Journal of Clinical Oncology. 1998 ; Vol. 16, No. 4. pp. 1450-1457.
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abstract = "Purpose: To determine the highest dose of fluorouracil (5-FU) that could be safely administered with Eniluracil (776C85; Glaxo Wellcome Inc, Research Triangle Park, NC), an inactivator of dihydropyrimidine dehydrogenase (DPD), on a daily schedule for 5 days, and to define the toxicities of the combination and the pharmacokinetics of 5-FU when administered with 776C85. Patients and Methods: Patients with advanced solid tumors refractory to standard therapy were enrolled at two institutions. The study consisted of three periods designed to evaluate the safety, pharmacokinetics, and pharmacodynamics of 776C85 alone (period 1); the effects of 776C85 on the pharmacokinetics of 5-FU (period 2); and the maximum-tolerated dose (MTD) of 5-FU, with or without leucovorin, that could be safely administered with 776C85 (period 3). Cohorts of at least three patients each received oral 776C85 alone at doses of 3.7 mg/m2/d, 18.5 mg/m2/d and 0.74 mg/m2/d. After a 14-day washout period, each patient then received 776C85 daily for 3 days, with a single intravenous (IV) bolus dose of 5-FU 10 mg/m2 on day 2. After a second washout period, patients were treated with 776C85 daily for 7 days and 5-FU IV bolus on days 2 through 6. The starting dose of 5-FU 10 mg/m2/d was escalated until the MTD was determined. After determination of the MTD of 5- FU given with 776C85, oral leucovorin 50 mg/d on days 2 through 6 was added to determine the MTD of 5-FU with leucovorin in the presence of 776C85. Near the completion of the study, additional cohorts of patients were treated with 776C85 at 50 mg/d and oral 5-FU with or without leucovorin. Results: Sixty- five patients were enrolled onto the study and 60 were assessable for toxicity and response. Bone marrow suppression was the primary and dose- limiting toxicity of this regimen. Other toxicities included diarrhea, mucositis, anemia, anorexia, nausea, vomiting, and fatigue. 776C85 suppressed DPD activity in peripheral-blood mononuclear cells (PBMCs) by at least 90{\%} for at least 24 hours at all dose levels tested. In the presence of 776C85, 5-FU half-life was prolonged, clearance was reduced, and the drug displayed linear pharmacokinetics. Recommended doses for further testing on a daily for 5-day schedule are 776C85 10 mg/d with IV 5-FU 25 mg/m2/d; 776C85 10 mg/d with IV 5-FU 20 mg/m2/d plus leucovorin 50 mg/d; 776C85 50 mg/d with 5-FU given orally at 15 mg/m2/d with leucovorin at 50 mg/d. Conclusion: 5-FU can be safely administered with 776C85; however, the MTDs are considerably lower than those conventionally used, caused, at least in part, by marked alterations in 5-FU plasma pharmocokinetics.",
author = "Schilsky, {Richard L.} and John Hohneker and Ratain, {Mark J.} and Linda Janisch and Leslie Smetzer and Lucas, {Virgil Sol} and Khor, {Soo Peang} and Diasio, {Robert B} and {Von Hoff}, {Daniel D.} and Burris, {Howard A.}",
year = "1998",
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language = "English (US)",
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pages = "1450--1457",
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TY - JOUR

T1 - Phase I clinical and pharmacologic study of Eniluracil plus fluorouracil in patients with advanced cancer

AU - Schilsky, Richard L.

AU - Hohneker, John

AU - Ratain, Mark J.

AU - Janisch, Linda

AU - Smetzer, Leslie

AU - Lucas, Virgil Sol

AU - Khor, Soo Peang

AU - Diasio, Robert B

AU - Von Hoff, Daniel D.

AU - Burris, Howard A.

PY - 1998/4

Y1 - 1998/4

N2 - Purpose: To determine the highest dose of fluorouracil (5-FU) that could be safely administered with Eniluracil (776C85; Glaxo Wellcome Inc, Research Triangle Park, NC), an inactivator of dihydropyrimidine dehydrogenase (DPD), on a daily schedule for 5 days, and to define the toxicities of the combination and the pharmacokinetics of 5-FU when administered with 776C85. Patients and Methods: Patients with advanced solid tumors refractory to standard therapy were enrolled at two institutions. The study consisted of three periods designed to evaluate the safety, pharmacokinetics, and pharmacodynamics of 776C85 alone (period 1); the effects of 776C85 on the pharmacokinetics of 5-FU (period 2); and the maximum-tolerated dose (MTD) of 5-FU, with or without leucovorin, that could be safely administered with 776C85 (period 3). Cohorts of at least three patients each received oral 776C85 alone at doses of 3.7 mg/m2/d, 18.5 mg/m2/d and 0.74 mg/m2/d. After a 14-day washout period, each patient then received 776C85 daily for 3 days, with a single intravenous (IV) bolus dose of 5-FU 10 mg/m2 on day 2. After a second washout period, patients were treated with 776C85 daily for 7 days and 5-FU IV bolus on days 2 through 6. The starting dose of 5-FU 10 mg/m2/d was escalated until the MTD was determined. After determination of the MTD of 5- FU given with 776C85, oral leucovorin 50 mg/d on days 2 through 6 was added to determine the MTD of 5-FU with leucovorin in the presence of 776C85. Near the completion of the study, additional cohorts of patients were treated with 776C85 at 50 mg/d and oral 5-FU with or without leucovorin. Results: Sixty- five patients were enrolled onto the study and 60 were assessable for toxicity and response. Bone marrow suppression was the primary and dose- limiting toxicity of this regimen. Other toxicities included diarrhea, mucositis, anemia, anorexia, nausea, vomiting, and fatigue. 776C85 suppressed DPD activity in peripheral-blood mononuclear cells (PBMCs) by at least 90% for at least 24 hours at all dose levels tested. In the presence of 776C85, 5-FU half-life was prolonged, clearance was reduced, and the drug displayed linear pharmacokinetics. Recommended doses for further testing on a daily for 5-day schedule are 776C85 10 mg/d with IV 5-FU 25 mg/m2/d; 776C85 10 mg/d with IV 5-FU 20 mg/m2/d plus leucovorin 50 mg/d; 776C85 50 mg/d with 5-FU given orally at 15 mg/m2/d with leucovorin at 50 mg/d. Conclusion: 5-FU can be safely administered with 776C85; however, the MTDs are considerably lower than those conventionally used, caused, at least in part, by marked alterations in 5-FU plasma pharmocokinetics.

AB - Purpose: To determine the highest dose of fluorouracil (5-FU) that could be safely administered with Eniluracil (776C85; Glaxo Wellcome Inc, Research Triangle Park, NC), an inactivator of dihydropyrimidine dehydrogenase (DPD), on a daily schedule for 5 days, and to define the toxicities of the combination and the pharmacokinetics of 5-FU when administered with 776C85. Patients and Methods: Patients with advanced solid tumors refractory to standard therapy were enrolled at two institutions. The study consisted of three periods designed to evaluate the safety, pharmacokinetics, and pharmacodynamics of 776C85 alone (period 1); the effects of 776C85 on the pharmacokinetics of 5-FU (period 2); and the maximum-tolerated dose (MTD) of 5-FU, with or without leucovorin, that could be safely administered with 776C85 (period 3). Cohorts of at least three patients each received oral 776C85 alone at doses of 3.7 mg/m2/d, 18.5 mg/m2/d and 0.74 mg/m2/d. After a 14-day washout period, each patient then received 776C85 daily for 3 days, with a single intravenous (IV) bolus dose of 5-FU 10 mg/m2 on day 2. After a second washout period, patients were treated with 776C85 daily for 7 days and 5-FU IV bolus on days 2 through 6. The starting dose of 5-FU 10 mg/m2/d was escalated until the MTD was determined. After determination of the MTD of 5- FU given with 776C85, oral leucovorin 50 mg/d on days 2 through 6 was added to determine the MTD of 5-FU with leucovorin in the presence of 776C85. Near the completion of the study, additional cohorts of patients were treated with 776C85 at 50 mg/d and oral 5-FU with or without leucovorin. Results: Sixty- five patients were enrolled onto the study and 60 were assessable for toxicity and response. Bone marrow suppression was the primary and dose- limiting toxicity of this regimen. Other toxicities included diarrhea, mucositis, anemia, anorexia, nausea, vomiting, and fatigue. 776C85 suppressed DPD activity in peripheral-blood mononuclear cells (PBMCs) by at least 90% for at least 24 hours at all dose levels tested. In the presence of 776C85, 5-FU half-life was prolonged, clearance was reduced, and the drug displayed linear pharmacokinetics. Recommended doses for further testing on a daily for 5-day schedule are 776C85 10 mg/d with IV 5-FU 25 mg/m2/d; 776C85 10 mg/d with IV 5-FU 20 mg/m2/d plus leucovorin 50 mg/d; 776C85 50 mg/d with 5-FU given orally at 15 mg/m2/d with leucovorin at 50 mg/d. Conclusion: 5-FU can be safely administered with 776C85; however, the MTDs are considerably lower than those conventionally used, caused, at least in part, by marked alterations in 5-FU plasma pharmocokinetics.

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