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

Nancy T. Sklarin, Chetan D. Lathia, Laura Benson, William R. Grove, Sylvia Thomas, Javier Roca, Avi Israel Einzig, Peter H. Wiernik

Research output: Contribution to journalArticle

12 Citations (Scopus)

Abstract

CI-980 is a synthetic mitotic inhibitor that binds to the colchicine binding site of tubulin. It demonstrates broad activity against human and murine tumor models and shows no cross resistance with tumor models whose mechanism of resistance is mediated by P-glycoprotein (MDR-1). A phase I study was completed in 25 patients with solid tumors using a 24-hour infusion schedule, with courses repeated every 3 weeks. Eight dose levels were tested between 1.2 and 15.6 mg/m2. The maximum tolerated dose was 14.4 mg/m2. Neutropenia was dose-related but not dose-limiting; thrombocytopenia was infrequent. CNS toxicities were dose-limiting and consisted of dizziness, headache, loss of coordination, loss of consciousness, nervousness, and other symptoms. These events occurred near the end of the infusion and were reversible, usually within 24 hours. One patient who was to be treated at dose level X (intended dose was 19.2 mg/m2; actual dose was 15.6 mg/m2) became encephalopathic prior to completion of the infusion. Other adverse events included gastrointestinal toxicities (nausea, vomiting, anorexia, constipation, stomatitis, dyspepsia, bleeding, cheilitis), IV site erythema, fever, and fatigue. A partial response was observed in one patient with colon cancer and reductions in CA-125 levels were observed in 2 patients with ovarian cancer. Pharmacokinetics were linear and dose-proportional. Results indicate high systemic clearance and wide tissue distribution. Mean pharmacokinetic parameter values: T(1/2) = 5.52 hours, plasma clearance 1163 mL/min/m2, and Vd55 376 L/m2.

Original languageEnglish (US)
Pages (from-to)235-246
Number of pages12
JournalInvestigational New Drugs
Volume15
Issue number3
DOIs
StatePublished - Nov 3 1997

Fingerprint

Pharmacokinetics
Neoplasms
Cheilitis
Stomatitis
Maximum Tolerated Dose
Unconsciousness
Dyspepsia
Colchicine
Anorexia
Dizziness
Tissue Distribution
Constipation
Erythema
Tubulin
Neutropenia
Human Activities
Thrombocytopenia
Ovarian Neoplasms
Colonic Neoplasms
Nausea

Keywords

  • CI-980
  • Phase I
  • Solid tumors

ASJC Scopus subject areas

  • Molecular Medicine
  • Pharmacology

Cite this

Sklarin, N. T., Lathia, C. D., Benson, L., Grove, W. R., Thomas, S., Roca, J., ... Wiernik, P. H. (1997). A phase I trial and pharmacokinetic evaluation of CI-980 in patients with advanced solid tumors. Investigational New Drugs, 15(3), 235-246. https://doi.org/10.1023/A:1005854510468

A phase I trial and pharmacokinetic evaluation of CI-980 in patients with advanced solid tumors. / Sklarin, Nancy T.; Lathia, Chetan D.; Benson, Laura; Grove, William R.; Thomas, Sylvia; Roca, Javier; Einzig, Avi Israel; Wiernik, Peter H.

In: Investigational New Drugs, Vol. 15, No. 3, 03.11.1997, p. 235-246.

Research output: Contribution to journalArticle

Sklarin, NT, Lathia, CD, Benson, L, Grove, WR, Thomas, S, Roca, J, Einzig, AI & Wiernik, PH 1997, 'A phase I trial and pharmacokinetic evaluation of CI-980 in patients with advanced solid tumors', Investigational New Drugs, vol. 15, no. 3, pp. 235-246. https://doi.org/10.1023/A:1005854510468
Sklarin, Nancy T. ; Lathia, Chetan D. ; Benson, Laura ; Grove, William R. ; Thomas, Sylvia ; Roca, Javier ; Einzig, Avi Israel ; Wiernik, Peter H. / A phase I trial and pharmacokinetic evaluation of CI-980 in patients with advanced solid tumors. In: Investigational New Drugs. 1997 ; Vol. 15, No. 3. pp. 235-246.
@article{e7632522edc94974843609365cfc046a,
title = "A phase I trial and pharmacokinetic evaluation of CI-980 in patients with advanced solid tumors",
abstract = "CI-980 is a synthetic mitotic inhibitor that binds to the colchicine binding site of tubulin. It demonstrates broad activity against human and murine tumor models and shows no cross resistance with tumor models whose mechanism of resistance is mediated by P-glycoprotein (MDR-1). A phase I study was completed in 25 patients with solid tumors using a 24-hour infusion schedule, with courses repeated every 3 weeks. Eight dose levels were tested between 1.2 and 15.6 mg/m2. The maximum tolerated dose was 14.4 mg/m2. Neutropenia was dose-related but not dose-limiting; thrombocytopenia was infrequent. CNS toxicities were dose-limiting and consisted of dizziness, headache, loss of coordination, loss of consciousness, nervousness, and other symptoms. These events occurred near the end of the infusion and were reversible, usually within 24 hours. One patient who was to be treated at dose level X (intended dose was 19.2 mg/m2; actual dose was 15.6 mg/m2) became encephalopathic prior to completion of the infusion. Other adverse events included gastrointestinal toxicities (nausea, vomiting, anorexia, constipation, stomatitis, dyspepsia, bleeding, cheilitis), IV site erythema, fever, and fatigue. A partial response was observed in one patient with colon cancer and reductions in CA-125 levels were observed in 2 patients with ovarian cancer. Pharmacokinetics were linear and dose-proportional. Results indicate high systemic clearance and wide tissue distribution. Mean pharmacokinetic parameter values: T(1/2) = 5.52 hours, plasma clearance 1163 mL/min/m2, and Vd55 376 L/m2.",
keywords = "CI-980, Phase I, Solid tumors",
author = "Sklarin, {Nancy T.} and Lathia, {Chetan D.} and Laura Benson and Grove, {William R.} and Sylvia Thomas and Javier Roca and Einzig, {Avi Israel} and Wiernik, {Peter H.}",
year = "1997",
month = "11",
day = "3",
doi = "10.1023/A:1005854510468",
language = "English (US)",
volume = "15",
pages = "235--246",
journal = "Investigational New Drugs",
issn = "0167-6997",
publisher = "Kluwer Academic Publishers",
number = "3",

}

TY - JOUR

T1 - A phase I trial and pharmacokinetic evaluation of CI-980 in patients with advanced solid tumors

AU - Sklarin, Nancy T.

AU - Lathia, Chetan D.

AU - Benson, Laura

AU - Grove, William R.

AU - Thomas, Sylvia

AU - Roca, Javier

AU - Einzig, Avi Israel

AU - Wiernik, Peter H.

PY - 1997/11/3

Y1 - 1997/11/3

N2 - CI-980 is a synthetic mitotic inhibitor that binds to the colchicine binding site of tubulin. It demonstrates broad activity against human and murine tumor models and shows no cross resistance with tumor models whose mechanism of resistance is mediated by P-glycoprotein (MDR-1). A phase I study was completed in 25 patients with solid tumors using a 24-hour infusion schedule, with courses repeated every 3 weeks. Eight dose levels were tested between 1.2 and 15.6 mg/m2. The maximum tolerated dose was 14.4 mg/m2. Neutropenia was dose-related but not dose-limiting; thrombocytopenia was infrequent. CNS toxicities were dose-limiting and consisted of dizziness, headache, loss of coordination, loss of consciousness, nervousness, and other symptoms. These events occurred near the end of the infusion and were reversible, usually within 24 hours. One patient who was to be treated at dose level X (intended dose was 19.2 mg/m2; actual dose was 15.6 mg/m2) became encephalopathic prior to completion of the infusion. Other adverse events included gastrointestinal toxicities (nausea, vomiting, anorexia, constipation, stomatitis, dyspepsia, bleeding, cheilitis), IV site erythema, fever, and fatigue. A partial response was observed in one patient with colon cancer and reductions in CA-125 levels were observed in 2 patients with ovarian cancer. Pharmacokinetics were linear and dose-proportional. Results indicate high systemic clearance and wide tissue distribution. Mean pharmacokinetic parameter values: T(1/2) = 5.52 hours, plasma clearance 1163 mL/min/m2, and Vd55 376 L/m2.

AB - CI-980 is a synthetic mitotic inhibitor that binds to the colchicine binding site of tubulin. It demonstrates broad activity against human and murine tumor models and shows no cross resistance with tumor models whose mechanism of resistance is mediated by P-glycoprotein (MDR-1). A phase I study was completed in 25 patients with solid tumors using a 24-hour infusion schedule, with courses repeated every 3 weeks. Eight dose levels were tested between 1.2 and 15.6 mg/m2. The maximum tolerated dose was 14.4 mg/m2. Neutropenia was dose-related but not dose-limiting; thrombocytopenia was infrequent. CNS toxicities were dose-limiting and consisted of dizziness, headache, loss of coordination, loss of consciousness, nervousness, and other symptoms. These events occurred near the end of the infusion and were reversible, usually within 24 hours. One patient who was to be treated at dose level X (intended dose was 19.2 mg/m2; actual dose was 15.6 mg/m2) became encephalopathic prior to completion of the infusion. Other adverse events included gastrointestinal toxicities (nausea, vomiting, anorexia, constipation, stomatitis, dyspepsia, bleeding, cheilitis), IV site erythema, fever, and fatigue. A partial response was observed in one patient with colon cancer and reductions in CA-125 levels were observed in 2 patients with ovarian cancer. Pharmacokinetics were linear and dose-proportional. Results indicate high systemic clearance and wide tissue distribution. Mean pharmacokinetic parameter values: T(1/2) = 5.52 hours, plasma clearance 1163 mL/min/m2, and Vd55 376 L/m2.

KW - CI-980

KW - Phase I

KW - Solid tumors

UR - http://www.scopus.com/inward/record.url?scp=0030679692&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=0030679692&partnerID=8YFLogxK

U2 - 10.1023/A:1005854510468

DO - 10.1023/A:1005854510468

M3 - Article

C2 - 9387046

AN - SCOPUS:0030679692

VL - 15

SP - 235

EP - 246

JO - Investigational New Drugs

JF - Investigational New Drugs

SN - 0167-6997

IS - 3

ER -