A phase I study of the dolastatin-15 analogue tasidotin (ILX651) administered intravenously daily for 5 consecutive days every 3 weeks in patients with advanced solid tumors

Scot Ebbinghaus, Eric Rubin, Evan M Hersh, Lee D Cranmer, Peter L. Bonate, Robert J. Fram, Antti Jekunen, Steve Weitman, Lisa A. Hammond

Research output: Contribution to journalArticle

38 Citations (Scopus)

Abstract

Purpose: To determine the maximum tolerated dose, dose-limiting toxicity, and pharmacokinetics of the dolastatin-15 analogue, tasidotin (ILX651), when administered i.v. daily for 5 days every 3 weeks. Experimental Design: Thirty-six patients with advanced solid tumors received a total of 114 courses through eight dose levels ranging from 2.3 to 36.3 mg/m2. Pharmacokinetic samples were collected in cycle 1. Results: Neutropenia was the principal dose-limiting toxicity at 36.3 mg/m2/d along with grade 3 ileus and elevated aspartate amino transaminase/alanine amino transaminase (n = 1). At the maximum tolerated dose, 27.3 mg/m2, 4 of 14 patients experienced dose-limiting grade 4 neutropenia. The other principal toxicities consisted of mild-to-moderate elevated transaminases, alopecia, fatigue, and nausea. One patient with melanoma metastatic to liver and bone treated at 15.4 mg/m2/d experienced a complete response and received 20 courses of tasidotin. Two other patients with melanoma had mixed responses of cutaneous metastases at 27.3 mg/m2/d associated with either stable or progressive visceral disease. In addition, nine patients had stable disease. There was no accumulation of tasidotin following repeated daily dosing. Tasidotin decayed from plasma in a biphasic fashion with a half-life of <45 minutes in most cases. Conclusion: The maximum tolerated dose and recommended phase II dose for tasidotin when administered on this schedule was 27.3 mg/m2/d. The favorable toxicity profile of tasidotin compared with other antitubulin agents (particularly the lack of severe cumulative neuropathy, peripheral edema, and fatigue), the observed antitumor activity of tasidotin, and its novel mechanism of action support further disease-directed evaluations of this agent on this 5-day schedule every 3 weeks.

Original languageEnglish (US)
Pages (from-to)7807-7816
Number of pages10
JournalClinical Cancer Research
Volume11
Issue number21
DOIs
StatePublished - Nov 1 2005

Fingerprint

Maximum Tolerated Dose
Neoplasms
Neutropenia
Fatigue
Melanoma
Appointments and Schedules
Pharmacokinetics
tasidotin
dolastatin 15
Ileus
Alopecia
Peripheral Nervous System Diseases
Aspartate Aminotransferases
Transaminases
Alanine Transaminase
Nausea
Half-Life
Edema
Research Design
Neoplasm Metastasis

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

A phase I study of the dolastatin-15 analogue tasidotin (ILX651) administered intravenously daily for 5 consecutive days every 3 weeks in patients with advanced solid tumors. / Ebbinghaus, Scot; Rubin, Eric; Hersh, Evan M; Cranmer, Lee D; Bonate, Peter L.; Fram, Robert J.; Jekunen, Antti; Weitman, Steve; Hammond, Lisa A.

In: Clinical Cancer Research, Vol. 11, No. 21, 01.11.2005, p. 7807-7816.

Research output: Contribution to journalArticle

Ebbinghaus, Scot ; Rubin, Eric ; Hersh, Evan M ; Cranmer, Lee D ; Bonate, Peter L. ; Fram, Robert J. ; Jekunen, Antti ; Weitman, Steve ; Hammond, Lisa A. / A phase I study of the dolastatin-15 analogue tasidotin (ILX651) administered intravenously daily for 5 consecutive days every 3 weeks in patients with advanced solid tumors. In: Clinical Cancer Research. 2005 ; Vol. 11, No. 21. pp. 7807-7816.
@article{d78f44b08d7d4c66bae659b5f478af50,
title = "A phase I study of the dolastatin-15 analogue tasidotin (ILX651) administered intravenously daily for 5 consecutive days every 3 weeks in patients with advanced solid tumors",
abstract = "Purpose: To determine the maximum tolerated dose, dose-limiting toxicity, and pharmacokinetics of the dolastatin-15 analogue, tasidotin (ILX651), when administered i.v. daily for 5 days every 3 weeks. Experimental Design: Thirty-six patients with advanced solid tumors received a total of 114 courses through eight dose levels ranging from 2.3 to 36.3 mg/m2. Pharmacokinetic samples were collected in cycle 1. Results: Neutropenia was the principal dose-limiting toxicity at 36.3 mg/m2/d along with grade 3 ileus and elevated aspartate amino transaminase/alanine amino transaminase (n = 1). At the maximum tolerated dose, 27.3 mg/m2, 4 of 14 patients experienced dose-limiting grade 4 neutropenia. The other principal toxicities consisted of mild-to-moderate elevated transaminases, alopecia, fatigue, and nausea. One patient with melanoma metastatic to liver and bone treated at 15.4 mg/m2/d experienced a complete response and received 20 courses of tasidotin. Two other patients with melanoma had mixed responses of cutaneous metastases at 27.3 mg/m2/d associated with either stable or progressive visceral disease. In addition, nine patients had stable disease. There was no accumulation of tasidotin following repeated daily dosing. Tasidotin decayed from plasma in a biphasic fashion with a half-life of <45 minutes in most cases. Conclusion: The maximum tolerated dose and recommended phase II dose for tasidotin when administered on this schedule was 27.3 mg/m2/d. The favorable toxicity profile of tasidotin compared with other antitubulin agents (particularly the lack of severe cumulative neuropathy, peripheral edema, and fatigue), the observed antitumor activity of tasidotin, and its novel mechanism of action support further disease-directed evaluations of this agent on this 5-day schedule every 3 weeks.",
author = "Scot Ebbinghaus and Eric Rubin and Hersh, {Evan M} and Cranmer, {Lee D} and Bonate, {Peter L.} and Fram, {Robert J.} and Antti Jekunen and Steve Weitman and Hammond, {Lisa A.}",
year = "2005",
month = "11",
day = "1",
doi = "10.1158/1078-0432.CCR-05-0909",
language = "English (US)",
volume = "11",
pages = "7807--7816",
journal = "Clinical Cancer Research",
issn = "1078-0432",
publisher = "American Association for Cancer Research Inc.",
number = "21",

}

TY - JOUR

T1 - A phase I study of the dolastatin-15 analogue tasidotin (ILX651) administered intravenously daily for 5 consecutive days every 3 weeks in patients with advanced solid tumors

AU - Ebbinghaus, Scot

AU - Rubin, Eric

AU - Hersh, Evan M

AU - Cranmer, Lee D

AU - Bonate, Peter L.

AU - Fram, Robert J.

AU - Jekunen, Antti

AU - Weitman, Steve

AU - Hammond, Lisa A.

PY - 2005/11/1

Y1 - 2005/11/1

N2 - Purpose: To determine the maximum tolerated dose, dose-limiting toxicity, and pharmacokinetics of the dolastatin-15 analogue, tasidotin (ILX651), when administered i.v. daily for 5 days every 3 weeks. Experimental Design: Thirty-six patients with advanced solid tumors received a total of 114 courses through eight dose levels ranging from 2.3 to 36.3 mg/m2. Pharmacokinetic samples were collected in cycle 1. Results: Neutropenia was the principal dose-limiting toxicity at 36.3 mg/m2/d along with grade 3 ileus and elevated aspartate amino transaminase/alanine amino transaminase (n = 1). At the maximum tolerated dose, 27.3 mg/m2, 4 of 14 patients experienced dose-limiting grade 4 neutropenia. The other principal toxicities consisted of mild-to-moderate elevated transaminases, alopecia, fatigue, and nausea. One patient with melanoma metastatic to liver and bone treated at 15.4 mg/m2/d experienced a complete response and received 20 courses of tasidotin. Two other patients with melanoma had mixed responses of cutaneous metastases at 27.3 mg/m2/d associated with either stable or progressive visceral disease. In addition, nine patients had stable disease. There was no accumulation of tasidotin following repeated daily dosing. Tasidotin decayed from plasma in a biphasic fashion with a half-life of <45 minutes in most cases. Conclusion: The maximum tolerated dose and recommended phase II dose for tasidotin when administered on this schedule was 27.3 mg/m2/d. The favorable toxicity profile of tasidotin compared with other antitubulin agents (particularly the lack of severe cumulative neuropathy, peripheral edema, and fatigue), the observed antitumor activity of tasidotin, and its novel mechanism of action support further disease-directed evaluations of this agent on this 5-day schedule every 3 weeks.

AB - Purpose: To determine the maximum tolerated dose, dose-limiting toxicity, and pharmacokinetics of the dolastatin-15 analogue, tasidotin (ILX651), when administered i.v. daily for 5 days every 3 weeks. Experimental Design: Thirty-six patients with advanced solid tumors received a total of 114 courses through eight dose levels ranging from 2.3 to 36.3 mg/m2. Pharmacokinetic samples were collected in cycle 1. Results: Neutropenia was the principal dose-limiting toxicity at 36.3 mg/m2/d along with grade 3 ileus and elevated aspartate amino transaminase/alanine amino transaminase (n = 1). At the maximum tolerated dose, 27.3 mg/m2, 4 of 14 patients experienced dose-limiting grade 4 neutropenia. The other principal toxicities consisted of mild-to-moderate elevated transaminases, alopecia, fatigue, and nausea. One patient with melanoma metastatic to liver and bone treated at 15.4 mg/m2/d experienced a complete response and received 20 courses of tasidotin. Two other patients with melanoma had mixed responses of cutaneous metastases at 27.3 mg/m2/d associated with either stable or progressive visceral disease. In addition, nine patients had stable disease. There was no accumulation of tasidotin following repeated daily dosing. Tasidotin decayed from plasma in a biphasic fashion with a half-life of <45 minutes in most cases. Conclusion: The maximum tolerated dose and recommended phase II dose for tasidotin when administered on this schedule was 27.3 mg/m2/d. The favorable toxicity profile of tasidotin compared with other antitubulin agents (particularly the lack of severe cumulative neuropathy, peripheral edema, and fatigue), the observed antitumor activity of tasidotin, and its novel mechanism of action support further disease-directed evaluations of this agent on this 5-day schedule every 3 weeks.

UR - http://www.scopus.com/inward/record.url?scp=27744536541&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=27744536541&partnerID=8YFLogxK

U2 - 10.1158/1078-0432.CCR-05-0909

DO - 10.1158/1078-0432.CCR-05-0909

M3 - Article

C2 - 16278403

AN - SCOPUS:27744536541

VL - 11

SP - 7807

EP - 7816

JO - Clinical Cancer Research

JF - Clinical Cancer Research

SN - 1078-0432

IS - 21

ER -