Phase I clinical trial of continuous infusion cyclopentenyl cytosine

Pedro M. Politi, Fuming Xie, William Dahut, Harry Ford, James A. Kelley, Anne Bastian, Ann Setser, Carmen J. Allegra, Alice P. Chen, J. Michael Hamilton, Susan F. Arbuck, Peter Linz, Harry Brammer, Jean L. Grem

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Abstract

Cyclopentenyl cytosine (CPE-C) is an investigational drug that is active against human solid tumor xenografts. The 5′-triphosphate of CPE-C inhibits CTP synthase, and depletes CTP and dCTP pools. We conducted a phase I clinical trial of CPE-C given as a 24-h continuous i. v. infusion every 3 weeks in 26 adults with solid tumors. The starting dose rate, 1 mg/m2 per h, was selected on the basis of both preclinical studies and pharmacokinetic data from two patients obtained after a test dose of 24 mg/m2 CPE-C as an i. v. bolus. Dose escalation was guided by clinical toxicity. A total of 87 cycles were given, and ten patients received four or more cycles. The mean CPE-C steady-state plasma levels (Cpss) increased linearly from 0.4 μM to 3.1 μM at dose levels ranging from 1 to 5.9 mg/m2 per h (actual body weight); the mean total body clearance was 146±38 ml/min per m2. CPE-C was eliminated by both renal excretion of intact drug and deamination to cyclopentenyl uracil in an apparent 2:1 ratio. CTP synthase activity in intact bone marrow mononuclear cells was inhibited by 58% to 100% at 22 h compared to matched pretreatment samples at all CPE-C dose levels. When all data were combined, flux through CTP synthase was decreased by 89.6%±3.1% at 22h (mean ± SE, n=16), and remained inhibited by 67.6%±7.7% (n=10) for at least 24 h post-CPE-C infusion. Granulocyte and platelet toxicities were dose-dependent, and dose-limiting myelosuppression occurred during the initial cycle in two of three patients treated with 5.9 mg/m2 per h. Four of 11 patients (4 of 20 cycles) who received 4.7 mg/m2 per h CPE-C experienced hypotension 24-48 h after completion of the CPE-C infusion during their first (n=2), third (n=1) and sixth cycles (n=1), respectively. Two of these patients died with refractory hypotension despite aggressive hydration and cardiopulmonary resuscitation. One of 12 patients (28 total cycles) treated with 3.5 mg/m2 per h CPE-C experienced orthostatic hypotension during cycle 1, and this patient had a second episode of orthostatic hypotension at a lower dose (3.0 mg/m2per h). Hypotension was not seen in patients receiving ≤2.5 mg/m2 per h CPE-C. The occurrence of hypotension did not directly correlate with either CPE-C Cpss, CPE-U plasma levels, pretreatment cytidine plasma levels, baseline CTP synthase activity, or with the degree of enzyme inhibition during treatment. While the hypotension appeared to be dose-related, its unpredictable occurrence and the uncertainty concerning the mechanism preclude a recommendation of a tolerable dose for future studies.

Original languageEnglish (US)
Pages (from-to)513-523
Number of pages11
JournalCancer Chemotherapy and Pharmacology
Volume36
Issue number6
DOIs
StatePublished - Nov 1 1995

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Keywords

  • CTP synthase
  • Cyclopentenyl cytosine
  • Hypotension
  • Pharmacokinetics
  • Phase I trials

ASJC Scopus subject areas

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

Cite this

Politi, P. M., Xie, F., Dahut, W., Ford, H., Kelley, J. A., Bastian, A., Setser, A., Allegra, C. J., Chen, A. P., Hamilton, J. M., Arbuck, S. F., Linz, P., Brammer, H., & Grem, J. L. (1995). Phase I clinical trial of continuous infusion cyclopentenyl cytosine. Cancer Chemotherapy and Pharmacology, 36(6), 513-523. https://doi.org/10.1007/BF00685802