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A phase I trial and pharmacokinetic evaluation of CI-980 in patients with advanced solid tumors

N T Sklarin1, C D Lathia, L Benson

  • 1Albert Einstein Cancer Center, Bronx, New York, USA.

Investigational New Drugs
|January 1, 1997
PubMed

Insights

CI-980, a novel mitotic inhibitor, showed anti-tumor activity in preclinical models and was tested in a Phase I study. The maximum tolerated dose was 14.4 mg/m2, with dose-limiting CNS toxicities observed.

Area of Science:

  • Oncology
  • Pharmacology
  • Molecular Biology

Background:

  • CI-980 is a synthetic mitotic inhibitor targeting the colchicine binding site of tubulin.
  • It exhibits broad-spectrum anti-tumor activity in human and murine models.
  • CI-980 demonstrates no cross-resistance with P-glycoprotein-mediated multidrug resistance (MDR-1) mechanisms.

Purpose of the Study:

  • To evaluate the safety, tolerability, and pharmacokinetics of CI-980 in patients with solid tumors.
  • To determine the maximum tolerated dose (MTD) of CI-980 using a 24-hour infusion schedule.
  • To assess preliminary anti-tumor activity of CI-980.

Main Methods:

  • A Phase I clinical trial was conducted in 25 patients with solid tumors.
  • CI-980 was administered via a 24-hour infusion every 3 weeks.
  • Eight dose levels ranging from 1.2 to 15.6 mg/m2 were evaluated to determine the MTD.

Main Results:

  • The MTD of CI-980 was determined to be 14.4 mg/m2.
  • Dose-limiting central nervous system (CNS) toxicities, including dizziness and loss of consciousness, were observed and were reversible.
  • Neutropenia was dose-related but not dose-limiting; gastrointestinal toxicities and IV site erythema were also reported.
  • Pharmacokinetics were linear and dose-proportional, with high systemic clearance and wide tissue distribution.
  • Preliminary efficacy included a partial response in colon cancer and CA-125 reductions in ovarian cancer patients.

Conclusions:

  • CI-980 is a novel mitotic inhibitor with a defined MTD and manageable toxicity profile.
  • The drug demonstrated dose-limiting CNS toxicities, necessitating careful monitoring during infusion.
  • Further investigation of CI-980 in specific tumor types is warranted based on preliminary activity and favorable pharmacokinetic properties.

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