Phase I trial and clinical pharmacological evaluation of hexamethylene bisacetamide administration by ten-day continuous intravenous infusion at twenty-eight-day intervals Journal Article


Authors: Young, C. W.; Fanucchi, M. P.; Walsh, T. D.; Baltzer, L.; Yaldaei, S.; Stevens, Y. W.; Gordon, C.; Tong, W.; Rifkind, R. A.; Marks, P. A.
Article Title: Phase I trial and clinical pharmacological evaluation of hexamethylene bisacetamide administration by ten-day continuous intravenous infusion at twenty-eight-day intervals
Abstract: We have treated 33 patients with different types of advanced cancer by 10-day continuous i.v. infusion courses of hexamethylene bisacetamide (HMBA), a drug that produces differentiation of a variety of transformed cell lines on prolonged exposure in vitro to drug concentrations of 3 to 5 mM. In this dose-finding and pharmacokinetic study, five dosage levels were explored from 12 to 28 g/m2/day. Patients who had not shown progression of disease were given repeat courses of therapy at 28-day intervals. Seventy-two courses of therapy were administered; 17 patients received one course; eight patients received two; six patients received three; and one patient each received four and 17+ courses, respectively. The maximal tolerated dose was 28 g/m2/day for 10 days; the dose-limiting toxic effects were thrombocytopenia with hemorrhage and central nervous system dysfunction manifesting as disorientation and confusion. Based on these studies the recommended dosage for Phase II studies by the 10-day schedule is 24 g/m2/day. Pharmacokinetic studies demonstrated rapid clearance of HMBA from plasma; the decay phase data fit a one compartment model with a mean plasma half-life of 2.5 h and a range from 0.6 to 5.8 h. Mean plasma steady-state levels in our patients were 0.37, 0.38, 0.86, 0.88, and 1.42 mM, at the 12-, 16-, 20-, 24-, and 28-g/m2/day dosage levels, respectively. The data indicate that plasma HMBA concentrations of 1 mM can be maintained for 10 days with acceptable patient tolerance, but that HMBA concentrations in excess of 1.4 mM for 10 days are associated with substantial hematological and central nervous system toxicity. Objective antitumor effects were observed in five patients; one woman with non-small cell lung cancer, who has received 17+ courses over a period of 28+ mo, achieved a partial remission that continues at 28+ mo on therapy. Transient regression of cutaneous metastases was observed in three patients with breast carcinoma and one patient with colorectal carcinoma. © 1988, American Association for Cancer Research. All rights reserved.
Keywords: adult; clinical article; aged; advanced cancer; antineoplastic agents; cancer patient; neurotoxicity; neoplasms; thrombocytopenia; cell line; age; phase 1 clinical trial; drug therapy; infusions, intravenous; intravenous drug administration; middle age; drug evaluation; hexamethylenebisacetamide; acetamides; human; male; female; priority journal; support, non-u.s. gov't; support, u.s. gov't, p.h.s.
Journal Title: Cancer Research
Volume: 48
Issue: 24 Pt. 1
ISSN: 0008-5472
Publisher: American Association for Cancer Research  
Date Published: 1988-12-15
Start Page: 7304
End Page: 7309
Language: English
PUBMED: 3191501
PROVIDER: scopus
DOI/URL:
Notes: Article -- Export Date: 6 August 2020 -- Source: Scopus
Citation Impact
MSK Authors
  1. William Ping-Yiu Tong
    158 Tong
  2. Paul Marks
    185 Marks
  3. Richard Rifkind
    117 Rifkind
  4. Charles W Young
    64 Young
  5. Clara Gordon
    2 Gordon