Tirapazamine plus carboplatin and paclitaxel in advanced malignant solid tumors: A California Cancer Consortium phase I and molecular correlative study

Primo N Lara, Paul Frankel, Philip Mack, Paul H. Gumerlock, Irina Galvin, Cynthia L. Martel, Jeff Longmate, James H. Doroshow, Heinz Josef Lenz, Derick H Lau, David R Gandara

Research output: Contribution to journalArticle

19 Citations (Scopus)

Abstract

Purpose: Tumor hypoxia confers chemotherapy resistance. Tirapazamine is a cytotoxin that selectively targets hypoxic cells and has supra-additive toxicity with platinums and taxanes in preclinical studies. We conducted a Phase I study of tirapazamine, carboplatin, and paclitaxel and assessed potential plasma markers of hypoxia as surrogates for response. Experimental Design: Forty-two patients with advanced solid tumors were treated at four dose levels; parallel dose escalations were carried out in chemotherapy-naive and previously treated subjects. Pre and post-therapy plasma levels of the hypoxia-induced proteins plasminogen activator inhibitor-1 and vascular endothelial growth factor were measured. Results: Three of four chemotherapy-naïve patients developed dose-limiting toxicities at dose level 4 (grade 3 stomatitis/infection, grade 3 emesis, and grade 4 febrile neutropenia). Four of seven previously treated patients developed dose-limiting toxicities at dose level 3, including one death [grade 3 myalgia, grade 3 infection/grade 4 neutropenia, grade 3 infection/grade 4 neutropenia, and grade 5 infection (death)/grade 4 neutropenia]. Of 38 patients assessable for response, 3 had a complete response, 1 a partial response, 1 an unconfirmed partial response, and 23 had stable disease in at least one evaluation; 10 quickly progressed. One complete responder had normalization of vascular endothelial growth factor and plasminogen activator inhibitor-1 levels. Conclusion: Dose levels 3 (carboplatin AUC of 6, 225 mg/m2 paclitaxel, and 330 mg/m2 tirapazamine) and 2 (carboplatin AUC 6, 225 mg/m2 paclitaxel, and 260 mg/m2 tirapazamine) are the maximum tolerated doses for chemotherapy naive and patients treated previously, respectively. Dose level 3 is the experimental arm of a Phase III Southwest Oncology Group trial (S0003) in advanced non-small cell lung cancer. Potential markers of tumor hypoxia may be useful correlates in studies of hypoxic cytotoxins and are being prospectively investigated in S0003.

Original languageEnglish (US)
Pages (from-to)4356-4362
Number of pages7
JournalClinical Cancer Research
Volume9
Issue number12
StatePublished - Oct 1 2003

Fingerprint

tirapazamine
Carboplatin
Paclitaxel
Neutropenia
Drug Therapy
Plasminogen Activator Inhibitor 1
Cytotoxins
Neoplasms
Infection
Vascular Endothelial Growth Factor A
Area Under Curve
Taxoids
Febrile Neutropenia
Stomatitis
Maximum Tolerated Dose
Myalgia
Non-Small Cell Lung Carcinoma
Vomiting
Research Design

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

Tirapazamine plus carboplatin and paclitaxel in advanced malignant solid tumors : A California Cancer Consortium phase I and molecular correlative study. / Lara, Primo N; Frankel, Paul; Mack, Philip; Gumerlock, Paul H.; Galvin, Irina; Martel, Cynthia L.; Longmate, Jeff; Doroshow, James H.; Lenz, Heinz Josef; Lau, Derick H; Gandara, David R.

In: Clinical Cancer Research, Vol. 9, No. 12, 01.10.2003, p. 4356-4362.

Research output: Contribution to journalArticle

Lara, Primo N ; Frankel, Paul ; Mack, Philip ; Gumerlock, Paul H. ; Galvin, Irina ; Martel, Cynthia L. ; Longmate, Jeff ; Doroshow, James H. ; Lenz, Heinz Josef ; Lau, Derick H ; Gandara, David R. / Tirapazamine plus carboplatin and paclitaxel in advanced malignant solid tumors : A California Cancer Consortium phase I and molecular correlative study. In: Clinical Cancer Research. 2003 ; Vol. 9, No. 12. pp. 4356-4362.
@article{6784a341e8e945e19f5dc36f2eda2e92,
title = "Tirapazamine plus carboplatin and paclitaxel in advanced malignant solid tumors: A California Cancer Consortium phase I and molecular correlative study",
abstract = "Purpose: Tumor hypoxia confers chemotherapy resistance. Tirapazamine is a cytotoxin that selectively targets hypoxic cells and has supra-additive toxicity with platinums and taxanes in preclinical studies. We conducted a Phase I study of tirapazamine, carboplatin, and paclitaxel and assessed potential plasma markers of hypoxia as surrogates for response. Experimental Design: Forty-two patients with advanced solid tumors were treated at four dose levels; parallel dose escalations were carried out in chemotherapy-naive and previously treated subjects. Pre and post-therapy plasma levels of the hypoxia-induced proteins plasminogen activator inhibitor-1 and vascular endothelial growth factor were measured. Results: Three of four chemotherapy-na{\"i}ve patients developed dose-limiting toxicities at dose level 4 (grade 3 stomatitis/infection, grade 3 emesis, and grade 4 febrile neutropenia). Four of seven previously treated patients developed dose-limiting toxicities at dose level 3, including one death [grade 3 myalgia, grade 3 infection/grade 4 neutropenia, grade 3 infection/grade 4 neutropenia, and grade 5 infection (death)/grade 4 neutropenia]. Of 38 patients assessable for response, 3 had a complete response, 1 a partial response, 1 an unconfirmed partial response, and 23 had stable disease in at least one evaluation; 10 quickly progressed. One complete responder had normalization of vascular endothelial growth factor and plasminogen activator inhibitor-1 levels. Conclusion: Dose levels 3 (carboplatin AUC of 6, 225 mg/m2 paclitaxel, and 330 mg/m2 tirapazamine) and 2 (carboplatin AUC 6, 225 mg/m2 paclitaxel, and 260 mg/m2 tirapazamine) are the maximum tolerated doses for chemotherapy naive and patients treated previously, respectively. Dose level 3 is the experimental arm of a Phase III Southwest Oncology Group trial (S0003) in advanced non-small cell lung cancer. Potential markers of tumor hypoxia may be useful correlates in studies of hypoxic cytotoxins and are being prospectively investigated in S0003.",
author = "Lara, {Primo N} and Paul Frankel and Philip Mack and Gumerlock, {Paul H.} and Irina Galvin and Martel, {Cynthia L.} and Jeff Longmate and Doroshow, {James H.} and Lenz, {Heinz Josef} and Lau, {Derick H} and Gandara, {David R}",
year = "2003",
month = "10",
day = "1",
language = "English (US)",
volume = "9",
pages = "4356--4362",
journal = "Clinical Cancer Research",
issn = "1078-0432",
publisher = "American Association for Cancer Research Inc.",
number = "12",

}

TY - JOUR

T1 - Tirapazamine plus carboplatin and paclitaxel in advanced malignant solid tumors

T2 - A California Cancer Consortium phase I and molecular correlative study

AU - Lara, Primo N

AU - Frankel, Paul

AU - Mack, Philip

AU - Gumerlock, Paul H.

AU - Galvin, Irina

AU - Martel, Cynthia L.

AU - Longmate, Jeff

AU - Doroshow, James H.

AU - Lenz, Heinz Josef

AU - Lau, Derick H

AU - Gandara, David R

PY - 2003/10/1

Y1 - 2003/10/1

N2 - Purpose: Tumor hypoxia confers chemotherapy resistance. Tirapazamine is a cytotoxin that selectively targets hypoxic cells and has supra-additive toxicity with platinums and taxanes in preclinical studies. We conducted a Phase I study of tirapazamine, carboplatin, and paclitaxel and assessed potential plasma markers of hypoxia as surrogates for response. Experimental Design: Forty-two patients with advanced solid tumors were treated at four dose levels; parallel dose escalations were carried out in chemotherapy-naive and previously treated subjects. Pre and post-therapy plasma levels of the hypoxia-induced proteins plasminogen activator inhibitor-1 and vascular endothelial growth factor were measured. Results: Three of four chemotherapy-naïve patients developed dose-limiting toxicities at dose level 4 (grade 3 stomatitis/infection, grade 3 emesis, and grade 4 febrile neutropenia). Four of seven previously treated patients developed dose-limiting toxicities at dose level 3, including one death [grade 3 myalgia, grade 3 infection/grade 4 neutropenia, grade 3 infection/grade 4 neutropenia, and grade 5 infection (death)/grade 4 neutropenia]. Of 38 patients assessable for response, 3 had a complete response, 1 a partial response, 1 an unconfirmed partial response, and 23 had stable disease in at least one evaluation; 10 quickly progressed. One complete responder had normalization of vascular endothelial growth factor and plasminogen activator inhibitor-1 levels. Conclusion: Dose levels 3 (carboplatin AUC of 6, 225 mg/m2 paclitaxel, and 330 mg/m2 tirapazamine) and 2 (carboplatin AUC 6, 225 mg/m2 paclitaxel, and 260 mg/m2 tirapazamine) are the maximum tolerated doses for chemotherapy naive and patients treated previously, respectively. Dose level 3 is the experimental arm of a Phase III Southwest Oncology Group trial (S0003) in advanced non-small cell lung cancer. Potential markers of tumor hypoxia may be useful correlates in studies of hypoxic cytotoxins and are being prospectively investigated in S0003.

AB - Purpose: Tumor hypoxia confers chemotherapy resistance. Tirapazamine is a cytotoxin that selectively targets hypoxic cells and has supra-additive toxicity with platinums and taxanes in preclinical studies. We conducted a Phase I study of tirapazamine, carboplatin, and paclitaxel and assessed potential plasma markers of hypoxia as surrogates for response. Experimental Design: Forty-two patients with advanced solid tumors were treated at four dose levels; parallel dose escalations were carried out in chemotherapy-naive and previously treated subjects. Pre and post-therapy plasma levels of the hypoxia-induced proteins plasminogen activator inhibitor-1 and vascular endothelial growth factor were measured. Results: Three of four chemotherapy-naïve patients developed dose-limiting toxicities at dose level 4 (grade 3 stomatitis/infection, grade 3 emesis, and grade 4 febrile neutropenia). Four of seven previously treated patients developed dose-limiting toxicities at dose level 3, including one death [grade 3 myalgia, grade 3 infection/grade 4 neutropenia, grade 3 infection/grade 4 neutropenia, and grade 5 infection (death)/grade 4 neutropenia]. Of 38 patients assessable for response, 3 had a complete response, 1 a partial response, 1 an unconfirmed partial response, and 23 had stable disease in at least one evaluation; 10 quickly progressed. One complete responder had normalization of vascular endothelial growth factor and plasminogen activator inhibitor-1 levels. Conclusion: Dose levels 3 (carboplatin AUC of 6, 225 mg/m2 paclitaxel, and 330 mg/m2 tirapazamine) and 2 (carboplatin AUC 6, 225 mg/m2 paclitaxel, and 260 mg/m2 tirapazamine) are the maximum tolerated doses for chemotherapy naive and patients treated previously, respectively. Dose level 3 is the experimental arm of a Phase III Southwest Oncology Group trial (S0003) in advanced non-small cell lung cancer. Potential markers of tumor hypoxia may be useful correlates in studies of hypoxic cytotoxins and are being prospectively investigated in S0003.

UR - http://www.scopus.com/inward/record.url?scp=10744226598&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=10744226598&partnerID=8YFLogxK

M3 - Article

C2 - 14555506

AN - SCOPUS:10744226598

VL - 9

SP - 4356

EP - 4362

JO - Clinical Cancer Research

JF - Clinical Cancer Research

SN - 1078-0432

IS - 12

ER -