Tirapazamine plus carboplatin and paclitaxel in advanced malignant solid tumors: a california cancer consortium phase I and molecular correlative study.
OBJECTIVE
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.


METHODS
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.


CONCLUSIONS
Dose levels 3 (carboplatin AUC of 6, 225 mg/m(2) paclitaxel, and 330 mg/m(2) tirapazamine) and 2 (carboplatin AUC 6, 225 mg/m(2) paclitaxel, and 260 mg/m(2) 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.
Lara
Primo N
PN
California Cancer Consortium at the University of California Davis Cancer Center, Sacramento, California 95817, USA. primo.lara@ucdmc.ucdavis.edu
Frankel
Paul
P
Mack
Philip C
PC
Gumerlock
Paul H
PH
Galvin
Irina
I
Martel
Cynthia L
CL
Longmate
Jeff
J
Doroshow
James H
JH
Lenz
Heinz Josef
HJ
Lau
Derick H M
DH
Gandara
David R
DR
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D016190:Carboplatin / Q000008:administration & dosage; D015687:Cell Hypoxia; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D006801:Humans; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D009369:Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D017239:Paclitaxel / Q000008:administration & dosage; D017395:Plasminogen Activator Inhibitor 1 / Q000097:blood*; D000077704:Tirapazamine; D014227:Triazines / Q000008:administration & dosage; D042461:Vascular Endothelial Growth Factor A / Q000097:blood*
D017395:Plasminogen Activator Inhibitor 1; D014227:Triazines; D042461:Vascular Endothelial Growth Factor A; D000077704:Tirapazamine; D016190:Carboplatin; D017239:Paclitaxel