Phase I clinical investigation of amonafide

R. Saez, J. B. Craig, J. G. Kuhn, G. R. Weiss, J. Koeller, J. Phillips, K. Havlin, G. Harman, J. Hardy, T. J. Melink, G. A. Sarosy, D. D. Von Hoff

Research output: Contribution to journalArticle

42 Citations (Scopus)

Abstract

Amonafide (benzisoquinolinedione, MSC 308847) is a new synthetic imide antineoplastic agent with DNA intercalative properties that has been evaluated in a phase I clinical trial. The drug was administered as a single intravenous (IV) infusion over 30 to 120 minutes repeated every 28 days. Ninety-five courses of therapy at doses ranging from 18 to 1,104 mg/m2 were administered to 38 patients with refractory solid tumors. Granulocytopenia was dose limiting. Leukopenia was seen in 13 of 31 courses at doses of 690 mg/m2 or greater. Life-threatening granulocytopenia (≤ 250 μL) was noted in 1/6 patients treated at 800 mg/m2, 1/8 patients treated at 918 mg/m2, and 2/5 patients treated at 1,104 mg/m2. No definite relationship between myelotoxicity and prior treatment status was noted. Rate-of-infusion dependent, nonhematologic toxicities included diaphoresis, flushing, dizziness and tinnitus, all of which were ameliorated by increasing the duration of drug infusion to 120 minutes. In addition, nausea and vomiting (grades 1 and 2) were seen in 29/56 courses at doses ≥ 519 mg/m2, but were easily controlled by phenothiazine antiemetics. Amonafide plasma and urine concentrations were determined by high-pressure liquid chromatography (HPLC). Plasma concentrations declined biexponentially with a terminal harmonic mean terminal half-life (t 1/2 ) of 5.5h. The mean apparent volume of distribution at steady-state and total body clearance were 532 L/m2 and 84 L/h/m2, respectively. Less than 5% of the total dose of amonafide was excreted unchanged in the urine. Antitumor activity has been noted in one patient with non-small-cell lung cancer (one complete response exceeding 29 months duration) and in one patient with prostatic cancer (complete pain relief and improvement in bone scan for 9 months). The recommended dose for phase II trials with this schedule of amonafide is 918 mg/m2 with dose escalation to myelotoxicity.

Original languageEnglish (US)
Pages (from-to)1351-1358
Number of pages8
JournalJournal of Clinical Oncology
Volume7
Issue number9
StatePublished - 1989

Fingerprint

amonafide
Agranulocytosis
Urine
Imides
Clinical Trials, Phase I
Antiemetics
Tinnitus
Leukopenia
Dizziness
Intravenous Infusions
Non-Small Cell Lung Carcinoma
Pharmaceutical Preparations
Antineoplastic Agents
Nausea
Vomiting
Half-Life
Prostatic Neoplasms
Appointments and Schedules
High Pressure Liquid Chromatography
Bone and Bones

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

Saez, R., Craig, J. B., Kuhn, J. G., Weiss, G. R., Koeller, J., Phillips, J., ... Von Hoff, D. D. (1989). Phase I clinical investigation of amonafide. Journal of Clinical Oncology, 7(9), 1351-1358.

Phase I clinical investigation of amonafide. / Saez, R.; Craig, J. B.; Kuhn, J. G.; Weiss, G. R.; Koeller, J.; Phillips, J.; Havlin, K.; Harman, G.; Hardy, J.; Melink, T. J.; Sarosy, G. A.; Von Hoff, D. D.

In: Journal of Clinical Oncology, Vol. 7, No. 9, 1989, p. 1351-1358.

Research output: Contribution to journalArticle

Saez, R, Craig, JB, Kuhn, JG, Weiss, GR, Koeller, J, Phillips, J, Havlin, K, Harman, G, Hardy, J, Melink, TJ, Sarosy, GA & Von Hoff, DD 1989, 'Phase I clinical investigation of amonafide', Journal of Clinical Oncology, vol. 7, no. 9, pp. 1351-1358.
Saez R, Craig JB, Kuhn JG, Weiss GR, Koeller J, Phillips J et al. Phase I clinical investigation of amonafide. Journal of Clinical Oncology. 1989;7(9):1351-1358.
Saez, R. ; Craig, J. B. ; Kuhn, J. G. ; Weiss, G. R. ; Koeller, J. ; Phillips, J. ; Havlin, K. ; Harman, G. ; Hardy, J. ; Melink, T. J. ; Sarosy, G. A. ; Von Hoff, D. D. / Phase I clinical investigation of amonafide. In: Journal of Clinical Oncology. 1989 ; Vol. 7, No. 9. pp. 1351-1358.
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abstract = "Amonafide (benzisoquinolinedione, MSC 308847) is a new synthetic imide antineoplastic agent with DNA intercalative properties that has been evaluated in a phase I clinical trial. The drug was administered as a single intravenous (IV) infusion over 30 to 120 minutes repeated every 28 days. Ninety-five courses of therapy at doses ranging from 18 to 1,104 mg/m2 were administered to 38 patients with refractory solid tumors. Granulocytopenia was dose limiting. Leukopenia was seen in 13 of 31 courses at doses of 690 mg/m2 or greater. Life-threatening granulocytopenia (≤ 250 μL) was noted in 1/6 patients treated at 800 mg/m2, 1/8 patients treated at 918 mg/m2, and 2/5 patients treated at 1,104 mg/m2. No definite relationship between myelotoxicity and prior treatment status was noted. Rate-of-infusion dependent, nonhematologic toxicities included diaphoresis, flushing, dizziness and tinnitus, all of which were ameliorated by increasing the duration of drug infusion to 120 minutes. In addition, nausea and vomiting (grades 1 and 2) were seen in 29/56 courses at doses ≥ 519 mg/m2, but were easily controlled by phenothiazine antiemetics. Amonafide plasma and urine concentrations were determined by high-pressure liquid chromatography (HPLC). Plasma concentrations declined biexponentially with a terminal harmonic mean terminal half-life (t 1/2 ) of 5.5h. The mean apparent volume of distribution at steady-state and total body clearance were 532 L/m2 and 84 L/h/m2, respectively. Less than 5{\%} of the total dose of amonafide was excreted unchanged in the urine. Antitumor activity has been noted in one patient with non-small-cell lung cancer (one complete response exceeding 29 months duration) and in one patient with prostatic cancer (complete pain relief and improvement in bone scan for 9 months). The recommended dose for phase II trials with this schedule of amonafide is 918 mg/m2 with dose escalation to myelotoxicity.",
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AU - Phillips, J.

AU - Havlin, K.

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AU - Von Hoff, D. D.

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