A phase I clinical and pharmacological profile of dacarbazine with autologous bone marrow transplantation in patients with solid tumors

Douglas R. Adkins, Rebecca Irvin, John Kuhn, David H. Boldt, G. David Roodman, Donna Salzman, Cesar Freytes, D. D. Von Hoff, C. F. LeMaistre

Research output: Contribution to journalArticle

7 Citations (Scopus)

Abstract

Dacarbazine (DTIC) is a chemotherapy drug which has antitumor activity at standard doses, exhibits a steep dose-response effect in vitro, and is associated with relatively few non-hematologic toxicities. These characteristics suggest a potential role for this drug in bone marrow transplant preparative regimens. To pursue this hypothesis, 16 patients with refractory solid tumors were enrolled in a phase I study of single agent DTIC to determine the dose of DTIC requiring bone marrow reinfusion and to define the dose-limiting toxicity and maximum tolerated dose when given with autologous bone marrow rescue. Pharmacokinetics were evaluated at the 4394 mg/m2 dose level. The marrow requiring dose was 2000 mg/m2 when given as a single intravenous (IV) infusion. The extramyeloid dose-limiting toxicity of DTIC was hypotension, with the maximum tolerated dose of DTIC being 3380 mg/m2 when given with bone marrow transplantation (BMT). Other toxicities were transient and tolerable. At 4394 mg/m2 of DTIC, plasma concentrations declined biexponentially with a terminal half-life of 3 hours. The mean clearance was 10.6 L/hr/m2 with a volume of distribution at steady state of 37.5 L/m2 and a mean maximum plasma concentration of 150 mcg/ml. One patient with melanoma developed a partial response of short duration after receiving 2600 mg/m2 of DTIC. Dacarbazine can be significantly dose escalated with an acceptable toxicity profile, when given with BMT. Future trials should focus on the addition of this drug to current BMT preparative regimens used for the treatment of patients with lymphoma.

Original languageEnglish (US)
Pages (from-to)169-179
Number of pages11
JournalInvestigational New Drugs
Volume11
Issue number2-3
DOIs
StatePublished - Jun 1993
Externally publishedYes

Fingerprint

Dacarbazine
Autologous Transplantation
Bone Marrow Transplantation
Pharmacology
Neoplasms
Bone Marrow
Maximum Tolerated Dose
Pharmaceutical Preparations
Intravenous Infusions
Hypotension
Half-Life
Melanoma
Lymphoma
Pharmacokinetics
Transplants
Drug Therapy

Keywords

  • autologous bone marrow transplantation
  • dacarbazine
  • solid tumors

ASJC Scopus subject areas

  • Pharmacology
  • Molecular Medicine

Cite this

A phase I clinical and pharmacological profile of dacarbazine with autologous bone marrow transplantation in patients with solid tumors. / Adkins, Douglas R.; Irvin, Rebecca; Kuhn, John; Boldt, David H.; Roodman, G. David; Salzman, Donna; Freytes, Cesar; Von Hoff, D. D.; LeMaistre, C. F.

In: Investigational New Drugs, Vol. 11, No. 2-3, 06.1993, p. 169-179.

Research output: Contribution to journalArticle

Adkins, DR, Irvin, R, Kuhn, J, Boldt, DH, Roodman, GD, Salzman, D, Freytes, C, Von Hoff, DD & LeMaistre, CF 1993, 'A phase I clinical and pharmacological profile of dacarbazine with autologous bone marrow transplantation in patients with solid tumors', Investigational New Drugs, vol. 11, no. 2-3, pp. 169-179. https://doi.org/10.1007/BF00874151
Adkins, Douglas R. ; Irvin, Rebecca ; Kuhn, John ; Boldt, David H. ; Roodman, G. David ; Salzman, Donna ; Freytes, Cesar ; Von Hoff, D. D. ; LeMaistre, C. F. / A phase I clinical and pharmacological profile of dacarbazine with autologous bone marrow transplantation in patients with solid tumors. In: Investigational New Drugs. 1993 ; Vol. 11, No. 2-3. pp. 169-179.
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