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 language | English (US) |
|---|---|
| Pages (from-to) | 4356-4362 |
| Number of pages | 7 |
| Journal | Clinical Cancer Research |
| Volume | 9 |
| Issue number | 12 |
| State | Published - Oct 1 2003 |
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ASJC Scopus subject areas
- Cancer Research
- Oncology
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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 journal › Article
}
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.
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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 -