A Phase I Study of Continuous Infusion 5-Fluorouracil plus Calcium Leucovorin in Combination with N-(Phosphonacetyl)-L-aspartate in Metastatic Gastrointestinal Adenocarcinoma

J. L. Grem, N. McAtee, S. M. Steinberg, J. M. Hamilton, R. F. Murphy, J. Drake, T. Chisena, F. Balis, R. Cysyk, S. G. Arbuck, J. M. Sorensen, A. P. Chen, L. Goldstein, E. Jordan, A. Setser, B. Goldspiel, C. J. Allegra

Research output: Contribution to journalArticle

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Abstract

Preclinical studies suggest that the biochemical effects of N-(phosphonacetyl)-L-aspartate (PALA), an inhibitor of aspartate carbamoyltransferase (ACTase), may increase the metabolic activation of 5-fluorouracil (5-FU) and enhance its cytotoxicity through both RNA- and DNA-directed mechanisms. In this Phase I trial, 22 evaluable patients with adenocarcinoma of the gastrointestinal tract were entered at escalating doses of 5-FU starting at 1150 mg/m2/day given as a concurrent 72-h i.v. infusion with a fixed dose of leucovorin (LCV), 500 mg/m2/day. The dose of 5-FU was escalated within patients according to individual tolerance, and then PALA at 250 mg/m2 was added 24 h prior to the initiation of the 5-FU/LCV infusion of the subsequent cycle. Dose-limiting mucositis and myelosuppression occurred during the initial cycle in 3 of 5 patients treated with 2300 mg/m2/day 5-FU; therefore, the recommended dose of 5-FU with concurrent LCV is 2000 mg/m2/day. Twenty-seven additional patients were then treated with escalating doses of PALA ranging from 375 to 2848 mg/m2, i.v., followed 24 h later by 2000 mg/m2/day 5-FU with high-dose LCV. Dose-limiting mucositis and myelosuppression occurred during the initial cycle in 2 of 3 patients entered at 2848 mg/m2 PALA. Dose-limiting mucositis and skin rash ultimately required both PALA and 5-FU dose reductions in 4 of 6 patients treated with 1899 mg/m2 PALA. Toxicity was similar, however, in patients receiving PALA at doses ranging from 375 to 1266 mg/m2. The mean steady-state plasma concentration of 5-FU at 2000 mg/m2/day was 6.5 ± 0.9 /am; patients with 5-FU levels >9 μ/m had a significantly higher incidence of serious gastrointestinal and hematological toxicity. Compared to each patient's own baseline, a significant trend for decreasing ACIase activity with increasing PALA dose was evident using cytosol isolated from peripheral blood mononuclear cells 24 h after PALA treatment (P2 = 0.01). PALA ≤844 mg/m2 failed to appreciably inhibit ACIase activity at 24 h in most patients; furthermore, a decrease in ACIase activity by >50% from baseline was seen in only 29% of cycles. More consistent inhibition of ACIase activity was seen with PALA ≥ 1266 mg/m2. Even with the highest PALA doses, however, ACIase activity returned to baseline by 96 h in most patients. In contrast, a modest decrease in plasma uridine levels was noted at all PALA doses, but the decrease was ≥50% in only 21% of cycles at 24 h. PALA ≤ 1266 mg/m2 could be safely combined with a 72-h i.v. infusion of 5-FU 2000 mg/m2/day with LCV 500 mg/m2/day starting 24 h after PALA. Because the delivered 5-FU dose intensity for patients entered at or above 1750 mg/m2/day in this trial was similar at PALA doses ≤ 1266 mg/m2, we have selected 1266 mg/m2 for future studies.

Original languageEnglish (US)
Pages (from-to)4828-4836
Number of pages9
JournalCancer Research
Volume53
Issue number20
StatePublished - Oct 1993

Fingerprint

NSC 224131
Leucovorin
Aspartic Acid
Fluorouracil
Adenocarcinoma
Mucositis

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

A Phase I Study of Continuous Infusion 5-Fluorouracil plus Calcium Leucovorin in Combination with N-(Phosphonacetyl)-L-aspartate in Metastatic Gastrointestinal Adenocarcinoma. / Grem, J. L.; McAtee, N.; Steinberg, S. M.; Hamilton, J. M.; Murphy, R. F.; Drake, J.; Chisena, T.; Balis, F.; Cysyk, R.; Arbuck, S. G.; Sorensen, J. M.; Chen, A. P.; Goldstein, L.; Jordan, E.; Setser, A.; Goldspiel, B.; Allegra, C. J.

In: Cancer Research, Vol. 53, No. 20, 10.1993, p. 4828-4836.

Research output: Contribution to journalArticle

Grem, JL, McAtee, N, Steinberg, SM, Hamilton, JM, Murphy, RF, Drake, J, Chisena, T, Balis, F, Cysyk, R, Arbuck, SG, Sorensen, JM, Chen, AP, Goldstein, L, Jordan, E, Setser, A, Goldspiel, B & Allegra, CJ 1993, 'A Phase I Study of Continuous Infusion 5-Fluorouracil plus Calcium Leucovorin in Combination with N-(Phosphonacetyl)-L-aspartate in Metastatic Gastrointestinal Adenocarcinoma', Cancer Research, vol. 53, no. 20, pp. 4828-4836.
Grem, J. L. ; McAtee, N. ; Steinberg, S. M. ; Hamilton, J. M. ; Murphy, R. F. ; Drake, J. ; Chisena, T. ; Balis, F. ; Cysyk, R. ; Arbuck, S. G. ; Sorensen, J. M. ; Chen, A. P. ; Goldstein, L. ; Jordan, E. ; Setser, A. ; Goldspiel, B. ; Allegra, C. J. / A Phase I Study of Continuous Infusion 5-Fluorouracil plus Calcium Leucovorin in Combination with N-(Phosphonacetyl)-L-aspartate in Metastatic Gastrointestinal Adenocarcinoma. In: Cancer Research. 1993 ; Vol. 53, No. 20. pp. 4828-4836.
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abstract = "Preclinical studies suggest that the biochemical effects of N-(phosphonacetyl)-L-aspartate (PALA), an inhibitor of aspartate carbamoyltransferase (ACTase), may increase the metabolic activation of 5-fluorouracil (5-FU) and enhance its cytotoxicity through both RNA- and DNA-directed mechanisms. In this Phase I trial, 22 evaluable patients with adenocarcinoma of the gastrointestinal tract were entered at escalating doses of 5-FU starting at 1150 mg/m2/day given as a concurrent 72-h i.v. infusion with a fixed dose of leucovorin (LCV), 500 mg/m2/day. The dose of 5-FU was escalated within patients according to individual tolerance, and then PALA at 250 mg/m2 was added 24 h prior to the initiation of the 5-FU/LCV infusion of the subsequent cycle. Dose-limiting mucositis and myelosuppression occurred during the initial cycle in 3 of 5 patients treated with 2300 mg/m2/day 5-FU; therefore, the recommended dose of 5-FU with concurrent LCV is 2000 mg/m2/day. Twenty-seven additional patients were then treated with escalating doses of PALA ranging from 375 to 2848 mg/m2, i.v., followed 24 h later by 2000 mg/m2/day 5-FU with high-dose LCV. Dose-limiting mucositis and myelosuppression occurred during the initial cycle in 2 of 3 patients entered at 2848 mg/m2 PALA. Dose-limiting mucositis and skin rash ultimately required both PALA and 5-FU dose reductions in 4 of 6 patients treated with 1899 mg/m2 PALA. Toxicity was similar, however, in patients receiving PALA at doses ranging from 375 to 1266 mg/m2. The mean steady-state plasma concentration of 5-FU at 2000 mg/m2/day was 6.5 ± 0.9 /am; patients with 5-FU levels >9 μ/m had a significantly higher incidence of serious gastrointestinal and hematological toxicity. Compared to each patient's own baseline, a significant trend for decreasing ACIase activity with increasing PALA dose was evident using cytosol isolated from peripheral blood mononuclear cells 24 h after PALA treatment (P2 = 0.01). PALA ≤844 mg/m2 failed to appreciably inhibit ACIase activity at 24 h in most patients; furthermore, a decrease in ACIase activity by >50{\%} from baseline was seen in only 29{\%} of cycles. More consistent inhibition of ACIase activity was seen with PALA ≥ 1266 mg/m2. Even with the highest PALA doses, however, ACIase activity returned to baseline by 96 h in most patients. In contrast, a modest decrease in plasma uridine levels was noted at all PALA doses, but the decrease was ≥50{\%} in only 21{\%} of cycles at 24 h. PALA ≤ 1266 mg/m2 could be safely combined with a 72-h i.v. infusion of 5-FU 2000 mg/m2/day with LCV 500 mg/m2/day starting 24 h after PALA. Because the delivered 5-FU dose intensity for patients entered at or above 1750 mg/m2/day in this trial was similar at PALA doses ≤ 1266 mg/m2, we have selected 1266 mg/m2 for future studies.",
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T1 - A Phase I Study of Continuous Infusion 5-Fluorouracil plus Calcium Leucovorin in Combination with N-(Phosphonacetyl)-L-aspartate in Metastatic Gastrointestinal Adenocarcinoma

AU - Grem, J. L.

AU - McAtee, N.

AU - Steinberg, S. M.

AU - Hamilton, J. M.

AU - Murphy, R. F.

AU - Drake, J.

AU - Chisena, T.

AU - Balis, F.

AU - Cysyk, R.

AU - Arbuck, S. G.

AU - Sorensen, J. M.

AU - Chen, A. P.

AU - Goldstein, L.

AU - Jordan, E.

AU - Setser, A.

AU - Goldspiel, B.

AU - Allegra, C. J.

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N2 - Preclinical studies suggest that the biochemical effects of N-(phosphonacetyl)-L-aspartate (PALA), an inhibitor of aspartate carbamoyltransferase (ACTase), may increase the metabolic activation of 5-fluorouracil (5-FU) and enhance its cytotoxicity through both RNA- and DNA-directed mechanisms. In this Phase I trial, 22 evaluable patients with adenocarcinoma of the gastrointestinal tract were entered at escalating doses of 5-FU starting at 1150 mg/m2/day given as a concurrent 72-h i.v. infusion with a fixed dose of leucovorin (LCV), 500 mg/m2/day. The dose of 5-FU was escalated within patients according to individual tolerance, and then PALA at 250 mg/m2 was added 24 h prior to the initiation of the 5-FU/LCV infusion of the subsequent cycle. Dose-limiting mucositis and myelosuppression occurred during the initial cycle in 3 of 5 patients treated with 2300 mg/m2/day 5-FU; therefore, the recommended dose of 5-FU with concurrent LCV is 2000 mg/m2/day. Twenty-seven additional patients were then treated with escalating doses of PALA ranging from 375 to 2848 mg/m2, i.v., followed 24 h later by 2000 mg/m2/day 5-FU with high-dose LCV. Dose-limiting mucositis and myelosuppression occurred during the initial cycle in 2 of 3 patients entered at 2848 mg/m2 PALA. Dose-limiting mucositis and skin rash ultimately required both PALA and 5-FU dose reductions in 4 of 6 patients treated with 1899 mg/m2 PALA. Toxicity was similar, however, in patients receiving PALA at doses ranging from 375 to 1266 mg/m2. The mean steady-state plasma concentration of 5-FU at 2000 mg/m2/day was 6.5 ± 0.9 /am; patients with 5-FU levels >9 μ/m had a significantly higher incidence of serious gastrointestinal and hematological toxicity. Compared to each patient's own baseline, a significant trend for decreasing ACIase activity with increasing PALA dose was evident using cytosol isolated from peripheral blood mononuclear cells 24 h after PALA treatment (P2 = 0.01). PALA ≤844 mg/m2 failed to appreciably inhibit ACIase activity at 24 h in most patients; furthermore, a decrease in ACIase activity by >50% from baseline was seen in only 29% of cycles. More consistent inhibition of ACIase activity was seen with PALA ≥ 1266 mg/m2. Even with the highest PALA doses, however, ACIase activity returned to baseline by 96 h in most patients. In contrast, a modest decrease in plasma uridine levels was noted at all PALA doses, but the decrease was ≥50% in only 21% of cycles at 24 h. PALA ≤ 1266 mg/m2 could be safely combined with a 72-h i.v. infusion of 5-FU 2000 mg/m2/day with LCV 500 mg/m2/day starting 24 h after PALA. Because the delivered 5-FU dose intensity for patients entered at or above 1750 mg/m2/day in this trial was similar at PALA doses ≤ 1266 mg/m2, we have selected 1266 mg/m2 for future studies.

AB - Preclinical studies suggest that the biochemical effects of N-(phosphonacetyl)-L-aspartate (PALA), an inhibitor of aspartate carbamoyltransferase (ACTase), may increase the metabolic activation of 5-fluorouracil (5-FU) and enhance its cytotoxicity through both RNA- and DNA-directed mechanisms. In this Phase I trial, 22 evaluable patients with adenocarcinoma of the gastrointestinal tract were entered at escalating doses of 5-FU starting at 1150 mg/m2/day given as a concurrent 72-h i.v. infusion with a fixed dose of leucovorin (LCV), 500 mg/m2/day. The dose of 5-FU was escalated within patients according to individual tolerance, and then PALA at 250 mg/m2 was added 24 h prior to the initiation of the 5-FU/LCV infusion of the subsequent cycle. Dose-limiting mucositis and myelosuppression occurred during the initial cycle in 3 of 5 patients treated with 2300 mg/m2/day 5-FU; therefore, the recommended dose of 5-FU with concurrent LCV is 2000 mg/m2/day. Twenty-seven additional patients were then treated with escalating doses of PALA ranging from 375 to 2848 mg/m2, i.v., followed 24 h later by 2000 mg/m2/day 5-FU with high-dose LCV. Dose-limiting mucositis and myelosuppression occurred during the initial cycle in 2 of 3 patients entered at 2848 mg/m2 PALA. Dose-limiting mucositis and skin rash ultimately required both PALA and 5-FU dose reductions in 4 of 6 patients treated with 1899 mg/m2 PALA. Toxicity was similar, however, in patients receiving PALA at doses ranging from 375 to 1266 mg/m2. The mean steady-state plasma concentration of 5-FU at 2000 mg/m2/day was 6.5 ± 0.9 /am; patients with 5-FU levels >9 μ/m had a significantly higher incidence of serious gastrointestinal and hematological toxicity. Compared to each patient's own baseline, a significant trend for decreasing ACIase activity with increasing PALA dose was evident using cytosol isolated from peripheral blood mononuclear cells 24 h after PALA treatment (P2 = 0.01). PALA ≤844 mg/m2 failed to appreciably inhibit ACIase activity at 24 h in most patients; furthermore, a decrease in ACIase activity by >50% from baseline was seen in only 29% of cycles. More consistent inhibition of ACIase activity was seen with PALA ≥ 1266 mg/m2. Even with the highest PALA doses, however, ACIase activity returned to baseline by 96 h in most patients. In contrast, a modest decrease in plasma uridine levels was noted at all PALA doses, but the decrease was ≥50% in only 21% of cycles at 24 h. PALA ≤ 1266 mg/m2 could be safely combined with a 72-h i.v. infusion of 5-FU 2000 mg/m2/day with LCV 500 mg/m2/day starting 24 h after PALA. Because the delivered 5-FU dose intensity for patients entered at or above 1750 mg/m2/day in this trial was similar at PALA doses ≤ 1266 mg/m2, we have selected 1266 mg/m2 for future studies.

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