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This report is a multi-institutional phase II study designed to obtain the response rate, survival, and toxicity profile for patients having hormone-refractory prostate cancer. Patients who had bidimensionally measurable prostate carcinoma in first or second remission after previous hormonal therapy but no history of chemotherapy were eligible. Patients were treated with leucovorin, 20 mg/m2 intravenously, followed by 5-fluorouracil (5-FU), 425 mg/m2 intravenously daily for 5 days, with cycles repeated every 28 days. Of 38 eligible patients, 3 (7.9%) had partial responses to therapy and 20 (52.6%) had stable disease. Median survival was 11.6 months for all 38 patients and median time to progression was 4.4 months. Most of the serious side effects were gastrointestinal or hematologic and overall, 23 of 38 patients (60.5%) experienced at least one grade 3 or 4 treatment-related toxicity of any type, as measured by the National Cancer Institute common toxicity criteria. Five patients (13.2%) withdrew from the study because of adverse reactions from chemotherapy. We conclude that treatment of hormone-refractory prostate cancer patients with 5-FU and leucovorin chemotherapy produced few responses at the cost of significant side effects. Further investigation of this combination is not warranted in this setting.

The results of several clinical trials support the hypothesis that biochemical modulation may enhance the antitumor activity of 5-Fluorouracil (5-FU). We have performed a phase I trial using a combination of three different biochemical modulators at the optimal dose established in previous clinical trials. The modulators include: phosphonacetyl-l-aspartate (PALA), which may increase 5-FU incorporation into RNA; leucovorin, which potentiates thymidylate synthase inhibition; and 6-methylmercaptopurine riboside (MMPR), which promotes the intracellular retention of fluorinated nucleotides. The treatment regimen consisted of PALA 250 mg/m2 day 1, followed 24 h later by MMPR 150 mg/m2 as an iv bolus, and the initiation of a 24-hour infusion of 5-FU along with leucovorin 50 mg/m2. This regimen was repeated weekly. Doses of 5-FU were escalated in cohorts of four or more patients from 2,000 to 2,600 mg/m2. Among 20 patients entered, the majority had colorectal cancer, and most had received prior 5-FU treatment. Toxicity was predominantly gastrointestinal, and diarrhea was dose-limiting at a 5-FU dose of 2600 mg/m2. There were three partial remissions observed, two of whom had colorectal cancer. Emerging data that casts doubt on the modulation value of PALA at this dose and schedule suggests that revision of this regimen be considered before Phase II trial.

Inhibition of pyrimidine and purine synthesis has been demonstrated to potentiate 5-fluorouracil (5-FU) activity in preclinical models. Low-dose phosphonacetyl-L-aspartate (PALA) potentiates the incorporation of 5-FU into RNA, without detectably increasing its toxicity. 6-Methylmercaptopurine riboside (MMPR) results in inhibition of purine biosynthesis with elevation of phosphoribosyl pyrophosphate (PRPP), which in turn is believed to increase the phosphorylation and intracellular retention of 5-FU. We conducted a phase I clinical trial to determine the maximum tolerated dose of 5-FU in combination with low-dose PALA and a biochemically-optimized dose of MMPR. The regimen consisted of PALA 250 mg/m2 given on day 1, followed 24 h later by MMPR 150 mg/m2, and escalating doses of 5-FU from 1625 to 2600 mg/m2 by 24 h continuous infusion. This regimen was repeated weekly. A group of 29 patients with a diagnosis of malignant solid tumor were entered; their median performance status was 1. The dose-limiting toxicity was mucositis, while other gastrointestinal toxicity was minimal. Two patients also experienced ischemic chest pain during the 5-FU infusion. The maximum tolerated dose of 5-FU in this combination was 2600 mg/m2. Several responses were observed including a complete remission in a previously treated breast cancer patient and two partial responses in breast and colon cancer. MMPR pharmacokinetics were obtained from urine analyses in 21 patients on this trial; there was no correlation between the pharmacokinetics of MMPR and the toxicity observed. This regimen was well tolerated and phase II trials are warranted using PALA 250 mg/m2, MMPR 150 mg/m2, and 5-FU 2300 mg/m2 by continuous infusion over 24 h.

A novel schedule of 5-fluorouracil administration has been developed for biochemical modulation studies. In combination with the pyrimidine synthesis inhibitor PALA, 5-fluorouracil has been given as a 24-hour infusion, repeated weekly: a dose of 2600 mg/m2 is well tolerated. To identify a suitable dose of 5-fluorouracil as a single agent on this schedule, we treated 26 patients at doses ranging from 2800 to 3400 mg/m2 per week. Two-thirds of the patients had failed previous therapy, and most were symptomatic from their disease. Over half of the patients had metastatic colorectal cancer. The dose-limiting toxicity was diarrhea: Grade 3 or 4 toxicity occurred at every level tested. Twenty-two of the 26 patients required therapy interruption because of toxicity. The severity of this toxicity indicated that escalation of 5-fluorouracil on this schedule beyond the 2600 mg/m2 known to be tolerated in the PALA-containing regimen, would be impractical. Two patients, both with previously untreated colorectal cancer, had partial remissions lasting three and five months respectively. This dose-intense schedule of 5-fluorouracil administration will be explored further in large-scale randomized trials.

In a phase II clinical trial of 5-fluorouracil (5FU) plus N-(phosphonacetyl)-L-aspartate (PALA) therapy administration, a number of slowly developing clinical responses were observed. Because of this, a variety of immune parameters were sequentially studied in 21 patients on this trial. Of the 21 patients studied, 20 provided sufficient samples to compare baseline with subsequent values, 10 of the 20 patients responded to treatment. Responders and non-responders did not differ in any studied parameter at baseline. After 2 months of therapy, non-specific monocyte cytotoxicity (NSMC), antibody-dependent monocyte cytotoxicity (ADMC) and natural killer (NK) activity were higher in the entire study population, but these increases were not statistically significant. When responders and non-responders were evaluated separately, it was apparent that the trend was due solely to the changes observed in the responding patient population. When mean lysis values for each patient group were determined for each studied time point, it was possible to generate a mean area under the cytotoxicity/time curve (AUC) for each studied parameter. NSMC and ADMC did not differ in responders and non-responders. However, NK activity was significantly greater by mean AUC analysis (P = 0.006) in the responding group; NK activity was maintained in the responders, but decreased in non-responders. When lymphocyte and monocyte expression of the surface markers beta 2-microglobulin, HLA-DR, CD56, HNK-1, CD16 and interleukin-2 receptor were evaluated, there were no differences among responders and non-responders at baseline by mean AUC analysis or when comparing baseline with non-baseline values. It is concluded that although baseline immunological characteristics do not identify patients who are likely to respond to weekly 5FU and PALA, treatment is not associated with deleterious effects on the immune effector function parameters evaluated in this study, there being no effects on expression of a variety of associated cell-surface molecules.

Low-dose phosphonacetyl-L-aspartate (PALA) may potentiate both 5-fluorouracil (5-FU) incorporation into RNA and thymidylate synthase inhibition by 5-fluorodeoxyuridylate (5-FdUMP). The gastrointestinal toxicity of 5-FU is not increased by PALA administration. Exogenous leucovorin, on the other hand, which enhances thymidylate synthase inhibition, appears to increase the clinical toxicity of 5-FU in a dose-dependent manner. As a result, the clinical use of high-dose leucovorin requires a marked dose reduction of 5-FU. Extracellular leucovorin levels of 1 microM suffice to maximize the enhancement of thymidylate synthase inhibition in several models. We conducted a trial to add leucovorin to the PALA/5-FU regimen. We chose a leucovorin dose that was predicted to yield end-infusion total reduced folate concentrations of 1 microM. The major endpoint was to determine the maximum tolerated dose of 5-FU in this combination. The regimen consisted of 250 mg/m2 PALA given on day 1 and, 24 h later, escalating 5-FU doses ranging from 1,850 to 2,600 mg/m2 admixed with 50 mg/m2 leucovorin and given by 24-h infusion. Courses were repeated weekly. A total of 24 patients with a median performance status of 1 were entered at three dose levels. Diarrhea was dose-limiting; 6/13 patients had grade II or worse diarrhea at 2,600 mg/m2. Dose modification resulted in a mean dose intensity of 2,300 mg/m2 at both the 2,600- and 2,300-mg/m2 dose levels. The 2,300-mg/m2 dose is suitable for phase II testing of this regimen. Three patients (two with breast cancer and 1 with sarcoma) had a partial remission. We measured steady-state concentrations (Css) of 5-FU in 23 patients. The mean Css increased with dose from 0.738 to 1.03 micrograms/ml. Total body clearance did not vary with dose in this range. Patients with grade II or worse diarrhea had a higher mean Css (1.10 +/- 0.19) than those with grade O or I toxicity (0.835 +/- 0.25, P < 0.02). Total bioactive folates (bound and free) were measured using a biological assay. Pretreatment values ranged from 2 to 52 nM and were not predictive of toxicity. End-infusion (23-h) values were somewhat lower than predicted and ranged from 400 to 950 nM. The risk of diarrhea was positively correlated with end-infusion total folate values. In a logistic regression analysis, total folate values obtained at 23 h were a more powerful predictor of diarrhea than were 5-FU Css values.(ABSTRACT TRUNCATED AT 400 WORDS) [ABSTRACT FROM AUTHOR]

Based on the synergy of sequential methotrexate (MTX) and 5-fluorouracil (5-FU) in vitro and in vivo and the superior antitumor activity of trimetrexate (TMTX) compared with MTX in preclinical models, we carried out a phase I trial of TMTX and 5-FU (fixed dose, 400 mg/m2 per day), both given as 10-min i.v. infusions daily x 5 days, every 28 days. The TMTX dose was escalated from 3.0 to 14.0 mg/m2 per day. In all, 92 evaluable courses were given to 34 patients, half of whom were heavily pretreated with radiation or cytotoxics. Myelosuppression and mucositis were the dose-limiting toxicities but were not different in heavily or minimally pretreated patients; there were five episodes of moderate to severe mucositis. Rash, fatigue, and diarrhea were mild toxicities. Plasma TMTX elimination was biexponential, with a mean t.1/2 alpha of 0.23 h and a t.1/2 beta of 16.7 h. The area under the plasma TMTX concentration versus time curve increased linearly with dose, suggesting first-order elimination. Total plasma TMTX clearance (mean +/- SD) was 14.3 +/- 5.9 ml/min per m2. Renal clearance accounted for approximately 7% of total clearance, indicating biotransformation as the major route of elimination. TMTX was highly protein-bound (97%). Thus, TMTX can be given with 5-FU (400 mg/m2) on a daily x 5-day bolus schedule at the 12 mg/m2 per day dose level, which was the recommended dose of TMTX as a single agent for phase II studies using the 5-day bolus schedule. [ABSTRACT FROM AUTHOR]