TY - JOUR
T1 - Pharmacokinetic and safety study of weekly irinotecan and oral capecitabine in patients with advanced solid cancers
AU - Goel, Sanjay
AU - Desai, Kavita
AU - Karri, Sirisha
AU - Gollamudi, Radharani
AU - Chaudhary, Imran
AU - Bulgaru, Anca
AU - Kaubisch, Andreas
AU - Goldberg, Gary
AU - Einstein, Mark
AU - Camacho, Fernando
AU - Baker, Sharyn
AU - Mani, Sridhar
N1 - Funding Information:
Acknowledgments This study is supported by a grant from Hoffmann-La Roche Inc and Pfizer Inc. SM is supported by a clinical investigator award from the Damon Runyon Cancer Research Foundation (CI: 15-02). ME is supported by a Clinical Mentored Research Scholar Program Award (K12 RR017672).
Copyright:
Copyright 2008 Elsevier B.V., All rights reserved.
PY - 2007/6
Y1 - 2007/6
N2 - Background: Capecitabine and irinotecan have demonstrated in vitro synergistic anti-cancer activity, and both are substrates for carboxyl esterases (CES). We conducted a study to identify a safe dose and potential drug-drug interactions of this combination. Methods: This was an open-label phase I dose escalation trial. Irinotecan was given as a 30 min infusion on days 1 and 8, and capecitabine on days 1-14 of a 21-day cycle. Plasma for pharmacokinetic analyses was drawn on days 1 and 8. Results: Forty-seven patients with advanced solid tumors received 202 cycles of chemotherapy in 6 dose cohorts. At the highest dose tested, 1 of 3 patients developed fatal neutropenia and gram-negative sepsis. At dose level 5 (100/2000), 2 of 28 patients developed cycle 1 DLT-grade 3 diarrhea/vomiting, and grade 3 diarrhea. Responses were observed in 9 of 35 (5 of 9 ovarian cancer) evaluable patients. The AUC (0-last) of irinotecan, SN-38G, and APC were similar on days 1 and 8. However, SN-38 Tmax was longer on Day 8 (0.88 h vs. 1.23 h, p = 0.012). While SN-38 AUC(0-last) was lower on day 8 by 35%, this was not statistically significant (p = 0.123). Conclusions: Capecitabine results in a significantly delayed conversion of irinotecan to SN-38, suggesting drug-drug interaction at the level of CES. This suggests caution should be used when irinotecan is combined with substrates of CES, and warrants further study. The combination of irinotecan and capecitabine is safe and well tolerated at 100/2000, and warrants further evaluation in ovarian and breast cancer.
AB - Background: Capecitabine and irinotecan have demonstrated in vitro synergistic anti-cancer activity, and both are substrates for carboxyl esterases (CES). We conducted a study to identify a safe dose and potential drug-drug interactions of this combination. Methods: This was an open-label phase I dose escalation trial. Irinotecan was given as a 30 min infusion on days 1 and 8, and capecitabine on days 1-14 of a 21-day cycle. Plasma for pharmacokinetic analyses was drawn on days 1 and 8. Results: Forty-seven patients with advanced solid tumors received 202 cycles of chemotherapy in 6 dose cohorts. At the highest dose tested, 1 of 3 patients developed fatal neutropenia and gram-negative sepsis. At dose level 5 (100/2000), 2 of 28 patients developed cycle 1 DLT-grade 3 diarrhea/vomiting, and grade 3 diarrhea. Responses were observed in 9 of 35 (5 of 9 ovarian cancer) evaluable patients. The AUC (0-last) of irinotecan, SN-38G, and APC were similar on days 1 and 8. However, SN-38 Tmax was longer on Day 8 (0.88 h vs. 1.23 h, p = 0.012). While SN-38 AUC(0-last) was lower on day 8 by 35%, this was not statistically significant (p = 0.123). Conclusions: Capecitabine results in a significantly delayed conversion of irinotecan to SN-38, suggesting drug-drug interaction at the level of CES. This suggests caution should be used when irinotecan is combined with substrates of CES, and warrants further study. The combination of irinotecan and capecitabine is safe and well tolerated at 100/2000, and warrants further evaluation in ovarian and breast cancer.
KW - Capecitabine
KW - Irinotecan
KW - Pharmacokinetics
KW - Phase I
KW - Solid tumors
UR - http://www.scopus.com/inward/record.url?scp=34248680725&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=34248680725&partnerID=8YFLogxK
U2 - 10.1007/s10637-006-9028-1
DO - 10.1007/s10637-006-9028-1
M3 - Article
C2 - 17195945
AN - SCOPUS:34248680725
SN - 0167-6997
VL - 25
SP - 237
EP - 245
JO - Investigational New Drugs
JF - Investigational New Drugs
IS - 3
ER -