Phase I trial of dolastatin-10 (NSC 376128) in patients with advanced solid tumors

Henry Clement Pitot, Edwin A. McElroy, Joel M Reid, Anthony John Windebank, Jeff A Sloan, Charles Erlichman, Pamela G. Bagniewski, Denise L. Walker, Joseph Rubin, Richard M. Goldberg, Alex Adjei, Matthew M. Ames

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Abstract

Dolastatin-10 (dola-10) is a potent antimitotic peptide, isolated from the marine mollusk Dolabela auricularia, that inhibits tubulin polymerization. Preclinical studies of dola-10 have demonstrated activity against a variety of murine and human tumors in cell cultures and mice models. The purpose of this Phase I clinical trial was to characterize the maximum tolerated dose, pharmacokinetics, and biological effects of dola-10 in patients with advanced solid tumors. Escalating doses of dola-10 were administered as an i.v. bolus every 21 days, using a modified Fibonacci dose escalation schema. Pharmacokinetic studies were performed with the first treatment cycle. Neurological testing was performed on each patient prior to treatment with dola-10, at 6 weeks and at study termination. Thirty eligible patients received a total of 94 cycles (median, 2 cycles; maximum, 14 cycles) of dola-10 at doses ranging from 65 to 455 μg/m2. Dose-limiting toxicity of granulocytopenia was seen at 455 μg/m2 for minimally pretreated patients (two or fewer prior chemotherapy regimens) and 325 μg/m2 for heavily pretreated patients (more than two prior chemotherapy regimens). Nonhematological toxicity was generally mild. Local irritation at the drug injection site was mild and not dose dependent. Nine patients developed new or increased symptoms of mild peripheral sensory neuropathy that was not dose limiting. This toxicity was more frequent in patients with preexisting peripheral neuropathies. Pharmacokinetic studies demonstrated a rapid drug distribution with a prolonged plasma elimination phase (t(1/2z) = 320 min). The area under the concentration-time curve increased in proportion to administered dose, whereas the clearance remained constant over the doses studied. Correlation analysis demonstrated a strong relationship between dola-10 area under the concentration-time curve values and decrease from baseline for leukocyte counts. In conclusion, dola-10 administered every 3 weeks as a peripheral i.v. bolus is well tolerated with dose-limiting toxicity of granulocytopenia. The maximum tolerated dose (and recommended Phase II starting dose) is 400 μg/m2 for patients with minimal prior treatment (two or fewer prior chemotherapy regimens) and 325 μg/m2 for patients who are heavily pretreated (more than two prior chemotherapy regimens).

Original languageEnglish (US)
Pages (from-to)525-531
Number of pages7
JournalClinical Cancer Research
Volume5
Issue number3
StatePublished - Mar 1999

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dolastatin 10
Neoplasms
Drug Therapy
Agranulocytosis
Maximum Tolerated Dose
Pharmacokinetics
Peripheral Nervous System Diseases
Antimitotic Agents
Clinical Trials, Phase I
Mollusca
Tubulin

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

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Phase I trial of dolastatin-10 (NSC 376128) in patients with advanced solid tumors. / Pitot, Henry Clement; McElroy, Edwin A.; Reid, Joel M; Windebank, Anthony John; Sloan, Jeff A; Erlichman, Charles; Bagniewski, Pamela G.; Walker, Denise L.; Rubin, Joseph; Goldberg, Richard M.; Adjei, Alex; Ames, Matthew M.

In: Clinical Cancer Research, Vol. 5, No. 3, 03.1999, p. 525-531.

Research output: Contribution to journalArticle

Pitot, HC, McElroy, EA, Reid, JM, Windebank, AJ, Sloan, JA, Erlichman, C, Bagniewski, PG, Walker, DL, Rubin, J, Goldberg, RM, Adjei, A & Ames, MM 1999, 'Phase I trial of dolastatin-10 (NSC 376128) in patients with advanced solid tumors', Clinical Cancer Research, vol. 5, no. 3, pp. 525-531.
Pitot, Henry Clement ; McElroy, Edwin A. ; Reid, Joel M ; Windebank, Anthony John ; Sloan, Jeff A ; Erlichman, Charles ; Bagniewski, Pamela G. ; Walker, Denise L. ; Rubin, Joseph ; Goldberg, Richard M. ; Adjei, Alex ; Ames, Matthew M. / Phase I trial of dolastatin-10 (NSC 376128) in patients with advanced solid tumors. In: Clinical Cancer Research. 1999 ; Vol. 5, No. 3. pp. 525-531.
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AU - Erlichman, Charles

AU - Bagniewski, Pamela G.

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