A phase I clinical and pharmacokinetic study of oral CI-1033 in combination with docetaxel in patients with advanced solid tumors.

Linda L Garland, Manuel Hidalgo, David S. Mendelson, David P. Ryan, Banu K. Arun, Jennifer L. Lovalvo, Irene A. Eiseman, Stephen C. Olson, Peter F. Lenehan, Joseph P. Eder

Research output: Contribution to journalArticle

21 Citations (Scopus)

Abstract

PURPOSE: CI-1033 is an orally available 4-anilinoquinazolone irreversible tyrosine kinase inhibitor of erbB-1, erbB-2, and erbB-4. We conducted a dose escalation study of CI-1033 with docetaxel to assess the safety profile and pharmacokinetics of the combination and to establish the maximum tolerated dose. EXPERIMENTAL DESIGN: Twenty-six patients with advanced solid tumors were treated on four dosing cohorts starting at CI-1033 (50 mg/d) + docetaxel (75 mg/m2). An intermittent dosing schedule avoided concurrent drug dosing. RESULTS: CI-1033 alone was escalated from 50 to 75 mg/d (dose level 2), where diarrhea was dose limiting; a 38% incidence of cycle 1 febrile neutropenia prompted dose de-escalation of both CI-1033 and docetaxel for dose level 3, where dose-limiting toxicities prompted further de-escalation of CI-1033 to 45 mg/d. Given equivalent safety profiles for dose level 1 [CI-1033 (50 mg/d) + docetaxel (75 mg/m2)] and dose level 4 [CI-1033 (45 mg/d) + docetaxel (60 mg/m2)], the former was determined to be the recommended phase II dose, given greater dose intensity of both drugs. Antitumor activity was noted in three patients, including a complete response in a patient with cervix uteri cancer. Pharmacokinetic analysis showed a possible effect of docetaxel on CI-1033 pharmacokinetics. CONCLUSIONS: It is feasible to combine the irreversible pan-erbB tyrosine kinase inhibitor CI-1033 with docetaxel on an intermittent dosing schedule in advanced cancer patients. We established the maximum tolerated dose and recommended phase II dose for the combination. Further investigation of this combination should include a rigorous analysis of the effect of docetaxel on CI-1033 pharmacokinetics.

Original languageEnglish (US)
Pages (from-to)4274-4282
Number of pages9
JournalClinical Cancer Research
Volume12
Issue number14 Pt 1
DOIs
StatePublished - Jul 15 2006

Fingerprint

docetaxel
Pharmacokinetics
Neoplasms
Maximum Tolerated Dose
Protein-Tyrosine Kinases
Appointments and Schedules
Clinical Studies
Canertinib
Safety
Febrile Neutropenia
Uterine Neoplasms

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

A phase I clinical and pharmacokinetic study of oral CI-1033 in combination with docetaxel in patients with advanced solid tumors. / Garland, Linda L; Hidalgo, Manuel; Mendelson, David S.; Ryan, David P.; Arun, Banu K.; Lovalvo, Jennifer L.; Eiseman, Irene A.; Olson, Stephen C.; Lenehan, Peter F.; Eder, Joseph P.

In: Clinical Cancer Research, Vol. 12, No. 14 Pt 1, 15.07.2006, p. 4274-4282.

Research output: Contribution to journalArticle

Garland, LL, Hidalgo, M, Mendelson, DS, Ryan, DP, Arun, BK, Lovalvo, JL, Eiseman, IA, Olson, SC, Lenehan, PF & Eder, JP 2006, 'A phase I clinical and pharmacokinetic study of oral CI-1033 in combination with docetaxel in patients with advanced solid tumors.', Clinical Cancer Research, vol. 12, no. 14 Pt 1, pp. 4274-4282. https://doi.org/10.1158/1078-0432.CCR-05-2507
Garland, Linda L ; Hidalgo, Manuel ; Mendelson, David S. ; Ryan, David P. ; Arun, Banu K. ; Lovalvo, Jennifer L. ; Eiseman, Irene A. ; Olson, Stephen C. ; Lenehan, Peter F. ; Eder, Joseph P. / A phase I clinical and pharmacokinetic study of oral CI-1033 in combination with docetaxel in patients with advanced solid tumors. In: Clinical Cancer Research. 2006 ; Vol. 12, No. 14 Pt 1. pp. 4274-4282.
@article{6fb413af28314a4facd3fa2ec00af7d6,
title = "A phase I clinical and pharmacokinetic study of oral CI-1033 in combination with docetaxel in patients with advanced solid tumors.",
abstract = "PURPOSE: CI-1033 is an orally available 4-anilinoquinazolone irreversible tyrosine kinase inhibitor of erbB-1, erbB-2, and erbB-4. We conducted a dose escalation study of CI-1033 with docetaxel to assess the safety profile and pharmacokinetics of the combination and to establish the maximum tolerated dose. EXPERIMENTAL DESIGN: Twenty-six patients with advanced solid tumors were treated on four dosing cohorts starting at CI-1033 (50 mg/d) + docetaxel (75 mg/m2). An intermittent dosing schedule avoided concurrent drug dosing. RESULTS: CI-1033 alone was escalated from 50 to 75 mg/d (dose level 2), where diarrhea was dose limiting; a 38{\%} incidence of cycle 1 febrile neutropenia prompted dose de-escalation of both CI-1033 and docetaxel for dose level 3, where dose-limiting toxicities prompted further de-escalation of CI-1033 to 45 mg/d. Given equivalent safety profiles for dose level 1 [CI-1033 (50 mg/d) + docetaxel (75 mg/m2)] and dose level 4 [CI-1033 (45 mg/d) + docetaxel (60 mg/m2)], the former was determined to be the recommended phase II dose, given greater dose intensity of both drugs. Antitumor activity was noted in three patients, including a complete response in a patient with cervix uteri cancer. Pharmacokinetic analysis showed a possible effect of docetaxel on CI-1033 pharmacokinetics. CONCLUSIONS: It is feasible to combine the irreversible pan-erbB tyrosine kinase inhibitor CI-1033 with docetaxel on an intermittent dosing schedule in advanced cancer patients. We established the maximum tolerated dose and recommended phase II dose for the combination. Further investigation of this combination should include a rigorous analysis of the effect of docetaxel on CI-1033 pharmacokinetics.",
author = "Garland, {Linda L} and Manuel Hidalgo and Mendelson, {David S.} and Ryan, {David P.} and Arun, {Banu K.} and Lovalvo, {Jennifer L.} and Eiseman, {Irene A.} and Olson, {Stephen C.} and Lenehan, {Peter F.} and Eder, {Joseph P.}",
year = "2006",
month = "7",
day = "15",
doi = "10.1158/1078-0432.CCR-05-2507",
language = "English (US)",
volume = "12",
pages = "4274--4282",
journal = "Clinical Cancer Research",
issn = "1078-0432",
publisher = "American Association for Cancer Research Inc.",
number = "14 Pt 1",

}

TY - JOUR

T1 - A phase I clinical and pharmacokinetic study of oral CI-1033 in combination with docetaxel in patients with advanced solid tumors.

AU - Garland, Linda L

AU - Hidalgo, Manuel

AU - Mendelson, David S.

AU - Ryan, David P.

AU - Arun, Banu K.

AU - Lovalvo, Jennifer L.

AU - Eiseman, Irene A.

AU - Olson, Stephen C.

AU - Lenehan, Peter F.

AU - Eder, Joseph P.

PY - 2006/7/15

Y1 - 2006/7/15

N2 - PURPOSE: CI-1033 is an orally available 4-anilinoquinazolone irreversible tyrosine kinase inhibitor of erbB-1, erbB-2, and erbB-4. We conducted a dose escalation study of CI-1033 with docetaxel to assess the safety profile and pharmacokinetics of the combination and to establish the maximum tolerated dose. EXPERIMENTAL DESIGN: Twenty-six patients with advanced solid tumors were treated on four dosing cohorts starting at CI-1033 (50 mg/d) + docetaxel (75 mg/m2). An intermittent dosing schedule avoided concurrent drug dosing. RESULTS: CI-1033 alone was escalated from 50 to 75 mg/d (dose level 2), where diarrhea was dose limiting; a 38% incidence of cycle 1 febrile neutropenia prompted dose de-escalation of both CI-1033 and docetaxel for dose level 3, where dose-limiting toxicities prompted further de-escalation of CI-1033 to 45 mg/d. Given equivalent safety profiles for dose level 1 [CI-1033 (50 mg/d) + docetaxel (75 mg/m2)] and dose level 4 [CI-1033 (45 mg/d) + docetaxel (60 mg/m2)], the former was determined to be the recommended phase II dose, given greater dose intensity of both drugs. Antitumor activity was noted in three patients, including a complete response in a patient with cervix uteri cancer. Pharmacokinetic analysis showed a possible effect of docetaxel on CI-1033 pharmacokinetics. CONCLUSIONS: It is feasible to combine the irreversible pan-erbB tyrosine kinase inhibitor CI-1033 with docetaxel on an intermittent dosing schedule in advanced cancer patients. We established the maximum tolerated dose and recommended phase II dose for the combination. Further investigation of this combination should include a rigorous analysis of the effect of docetaxel on CI-1033 pharmacokinetics.

AB - PURPOSE: CI-1033 is an orally available 4-anilinoquinazolone irreversible tyrosine kinase inhibitor of erbB-1, erbB-2, and erbB-4. We conducted a dose escalation study of CI-1033 with docetaxel to assess the safety profile and pharmacokinetics of the combination and to establish the maximum tolerated dose. EXPERIMENTAL DESIGN: Twenty-six patients with advanced solid tumors were treated on four dosing cohorts starting at CI-1033 (50 mg/d) + docetaxel (75 mg/m2). An intermittent dosing schedule avoided concurrent drug dosing. RESULTS: CI-1033 alone was escalated from 50 to 75 mg/d (dose level 2), where diarrhea was dose limiting; a 38% incidence of cycle 1 febrile neutropenia prompted dose de-escalation of both CI-1033 and docetaxel for dose level 3, where dose-limiting toxicities prompted further de-escalation of CI-1033 to 45 mg/d. Given equivalent safety profiles for dose level 1 [CI-1033 (50 mg/d) + docetaxel (75 mg/m2)] and dose level 4 [CI-1033 (45 mg/d) + docetaxel (60 mg/m2)], the former was determined to be the recommended phase II dose, given greater dose intensity of both drugs. Antitumor activity was noted in three patients, including a complete response in a patient with cervix uteri cancer. Pharmacokinetic analysis showed a possible effect of docetaxel on CI-1033 pharmacokinetics. CONCLUSIONS: It is feasible to combine the irreversible pan-erbB tyrosine kinase inhibitor CI-1033 with docetaxel on an intermittent dosing schedule in advanced cancer patients. We established the maximum tolerated dose and recommended phase II dose for the combination. Further investigation of this combination should include a rigorous analysis of the effect of docetaxel on CI-1033 pharmacokinetics.

UR - http://www.scopus.com/inward/record.url?scp=33846170171&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=33846170171&partnerID=8YFLogxK

U2 - 10.1158/1078-0432.CCR-05-2507

DO - 10.1158/1078-0432.CCR-05-2507

M3 - Article

C2 - 16857802

AN - SCOPUS:33846170171

VL - 12

SP - 4274

EP - 4282

JO - Clinical Cancer Research

JF - Clinical Cancer Research

SN - 1078-0432

IS - 14 Pt 1

ER -