Phase I trial of mitoxantrone and granulocyte-macrophage colony-stimulating factor (GM-CSF) in patients with advanced solid malignancies

Joan H. Schiller, Barry Storer, Rhoda Arzoomanian, Kendra Tutsch, Dona Alberti, David Spriggs

Research output: Contribution to journalArticle

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Abstract

Purpose: To determine the maximally tolerated dose (MTD) and pharmacokinetics of high-dose mitoxantrone and document the toxicities and side effects of mitoxantrone when administered with GM-CSF. Patients and methods: Twenty-three patients with advanced solid tumors were entered into a phase I and pharmacokinetic study. Mitoxantrone was administered at doses of 12, 21, 28, 32, 37, and 48 mg/m2 on day 1; GM-CSF (5 Μg/kg once or twice daily) was administered on days 2 to 14. Therapy was repeated every 3 weeks. Dose escalation continued in sets of three patients until the dose limiting toxicity (DLT) was observed. The DLT was based on hematologic, non-hematologic, and cardiac toxicity, and delay of therapy by more than 1 week due to toxicity. Plasma samples were assayed for mitoxantrone concentrations using high performance liquid chromatography (HPLC). Results: Twelve patients required either mitoxantrone dose reductions or delays. DLT of neutropenia was observed at a mitoxantrone dose of 48 mg/m2/day. Therefore, we conclude the MTD was 37 mg/m2/day. Myelosuppression appeared to be cumulative. Two patients were withdrawn from the study due to a drop in left ventricular ejection fraction (LVEF). Two of 23 patients experienced a partial response. The mean area under the curve (AUC) and peak mitoxantrone levels increased linearly with dose; triexponential elimination of mitoxantrone was observed. No statistically significant correlation was observed between either peak mitoxantrone level or AUC and duration of absolute neutrophil count (ANC) < 500/mm3. Conclusion: The use of GM-CSF allows administration of mitoxantrone at a dose greater than three times that given in standard therapy; treatment is well tolerated. Further studies are needed to determine whether mitoxantrone has cumulative cardiac or hematologic toxicity.

Original languageEnglish (US)
Pages (from-to)291-300
Number of pages10
JournalInvestigational New Drugs
Volume11
Issue number4
DOIs
StatePublished - Dec 1993

Fingerprint

Mitoxantrone
Granulocyte-Macrophage Colony-Stimulating Factor
Neoplasms
Maximum Tolerated Dose
Area Under Curve
Pharmacokinetics
Therapeutics
Neutropenia
Stroke Volume
Neutrophils
High Pressure Liquid Chromatography

Keywords

  • clinical trials
  • granulocyte-macrophage colony-stimulating factor
  • mitoxantrone
  • phase I trials

ASJC Scopus subject areas

  • Pharmacology
  • Molecular Medicine

Cite this

Phase I trial of mitoxantrone and granulocyte-macrophage colony-stimulating factor (GM-CSF) in patients with advanced solid malignancies. / Schiller, Joan H.; Storer, Barry; Arzoomanian, Rhoda; Tutsch, Kendra; Alberti, Dona; Spriggs, David.

In: Investigational New Drugs, Vol. 11, No. 4, 12.1993, p. 291-300.

Research output: Contribution to journalArticle

Schiller, Joan H. ; Storer, Barry ; Arzoomanian, Rhoda ; Tutsch, Kendra ; Alberti, Dona ; Spriggs, David. / Phase I trial of mitoxantrone and granulocyte-macrophage colony-stimulating factor (GM-CSF) in patients with advanced solid malignancies. In: Investigational New Drugs. 1993 ; Vol. 11, No. 4. pp. 291-300.
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AB - Purpose: To determine the maximally tolerated dose (MTD) and pharmacokinetics of high-dose mitoxantrone and document the toxicities and side effects of mitoxantrone when administered with GM-CSF. Patients and methods: Twenty-three patients with advanced solid tumors were entered into a phase I and pharmacokinetic study. Mitoxantrone was administered at doses of 12, 21, 28, 32, 37, and 48 mg/m2 on day 1; GM-CSF (5 Μg/kg once or twice daily) was administered on days 2 to 14. Therapy was repeated every 3 weeks. Dose escalation continued in sets of three patients until the dose limiting toxicity (DLT) was observed. The DLT was based on hematologic, non-hematologic, and cardiac toxicity, and delay of therapy by more than 1 week due to toxicity. Plasma samples were assayed for mitoxantrone concentrations using high performance liquid chromatography (HPLC). Results: Twelve patients required either mitoxantrone dose reductions or delays. DLT of neutropenia was observed at a mitoxantrone dose of 48 mg/m2/day. Therefore, we conclude the MTD was 37 mg/m2/day. Myelosuppression appeared to be cumulative. Two patients were withdrawn from the study due to a drop in left ventricular ejection fraction (LVEF). Two of 23 patients experienced a partial response. The mean area under the curve (AUC) and peak mitoxantrone levels increased linearly with dose; triexponential elimination of mitoxantrone was observed. No statistically significant correlation was observed between either peak mitoxantrone level or AUC and duration of absolute neutrophil count (ANC) < 500/mm3. Conclusion: The use of GM-CSF allows administration of mitoxantrone at a dose greater than three times that given in standard therapy; treatment is well tolerated. Further studies are needed to determine whether mitoxantrone has cumulative cardiac or hematologic toxicity.

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