Phase I study of capecitabine, oxaliplatin, bevacizumab, and everolimus in advanced solid tumors.
OBJECTIVE
To define maximum tolerated dose (MTD), toxicities, and pharmacodynamics of capecitabine, oxaliplatin, bevacizumab, and everolimus in advanced solid tumor patients.


METHODS
This was a standard "3 + 3" dose-escalation trial. All subjects received bevacizumab 7.5 mg/kg on day 1 of each cycle. Doses for capecitabine, oxaliplatin and everolimus were modified per dose limiting toxicity (DLT). Baseline and on-treatment plasma biomarkers were analyzed. Archived tumor mRNA levels were evaluated for NRP1, NRP2 and VEGF-A isoforms.


RESULTS
Twenty-nine patients were evaluable for toxicity and 30 for efficacy. Two DLTs were observed in cohort 1 and one DLT each was observed in cohort -1 and -1b. Grade ≥3 toxicities included neutropenia, hypertension, perforation/fistula/hemorrhage, hypertriglyceridemia, diarrhea, and thromboembolism. Twelve subjects experienced partial response (PR); 12 had stable disease as best response. Three of seven chemorefractory metastatic colorectal cancer (mCRC) subjects experienced PR; 8 of 15 chemonaive mCRC subjects experienced PR. Plasma TβRIII and IL-6 increased on treatment but without correlation to outcome. Increased VEGF165 levels significantly correlated with longer progression free survival.


CONCLUSIONS
Everolimus with full dose capecitabine, oxaliplatin, and bevacizumab had unacceptable toxicity. MTD was: everolimus 5 mg daily; capecitabine 680 mg/m(2) BID days 1-14; oxaliplatin 100 mg/m(2) and bevacizumab 7.5 mg/kg, day 1. Activity was noted in mCRC.
Duke University Medical Center, Seeley G. Mudd Bldg 10 Bryan Searle Drive, Box 3052, Durham, NC, 27710, USA.
Fatima
F
Rangwala
Johanna C
JC
Bendell
Mark F
MF
Kozloff
Christy C
CC
Arrowood
Andrew
A
Dellinger
Jennifer
J
Meadows
Sandra
S
Tourt-Uhlig
Jennifer
J
Murphy
Kellen L
KL
Meadows
Aijing
A
Starr
Samuel
S
Broderick
John C
JC
Brady
Stephanie M
SM
Cushman
Michael A
MA
Morse
Hope E
HE
Uronis
S David
SD
Hsu
S Yousuf
SY
Zafar
James
J
Wallace
Alexander N
AN
Starodub
John H
JH
Strickler
Herbert
H
Pang
Andrew B
AB
Nixon
Herbert I
HI
Hurwitz
D020533:Angiogenesis Inhibitors / Q000008:administration & dosage / Q000009:adverse effects; D061067:Antibodies, Monoclonal, Humanized / Q000008:administration & dosage / Q000009:adverse effects; D000964:Antimetabolites, Antineoplastic / Q000008:administration & dosage / Q000009:adverse effects; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000009:adverse effects; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage* / Q000009:adverse effects*; D000068258:Bevacizumab; D014408:Biomarkers, Tumor / Q000235:genetics / Q000378:metabolism; D000069287:Capecitabine; D003841:Deoxycytidine / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives; D000068338:Everolimus; D005260:Female; D005472:Fluorouracil / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives; D006801:Humans; D007166:Immunosuppressive Agents / Q000008:administration & dosage / Q000009:adverse effects; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D009369:Neoplasms / Q000188:drug therapy*; D039942:Neuropilin-1 / Q000235:genetics / Q000378:metabolism; D039943:Neuropilin-2 / Q000235:genetics / Q000378:metabolism; D009944:Organoplatinum Compounds / Q000008:administration & dosage / Q000009:adverse effects; D000077150:Oxaliplatin; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D020123:Sirolimus / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics / Q000378:metabolism
D020533:Angiogenesis Inhibitors; D061067:Antibodies, Monoclonal, Humanized; D000964:Antimetabolites, Antineoplastic; D000970:Antineoplastic Agents; D014408:Biomarkers, Tumor; D007166:Immunosuppressive Agents; D039943:Neuropilin-2; D009944:Organoplatinum Compounds; D012333:RNA, Messenger; C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A; C581308:neuropilin-2, human; D000077150:Oxaliplatin; D003841:Deoxycytidine; D039942:Neuropilin-1; D000068258:Bevacizumab; D000069287:Capecitabine; D000068338:Everolimus; D005472:Fluorouracil; D020123:Sirolimus