A phase I trial of nab-paclitaxel, gemcitabine, and capecitabine for metastatic pancreatic cancer.
BACKGROUND
Substantial antitumor activity has previously been demonstrated with the addition of nab-paclitaxel (Abraxane [Celgene, Summit, NJ]), an albumin-bound formulation of paclitaxel, to gemcitabine in patients with advanced pancreatic cancer. Given preclinical evidence of synergy when a fluoropyrimidine is added to gemcitabine plus a taxane in a sequence-specific schedule, we conducted a phase I study to evaluate the combination of nab-paclitaxel, gemcitabine, and capecitabine administered biweekly in patients with metastatic pancreatic adenocarcinoma.


METHODS
Patients with previously untreated metastatic pancreatic cancer and an ECOG performance status of 0-1 were eligible to participate. Study design utilized a 3 + 3 dose-escalation schema, with expanded cohort at maximum-tolerated dose (MTD). Treatment was administered in 14-day cycles, with capecitabine given on days 1-7 and both gemcitabine (at fixed-dose rate infusion) and nab-paclitaxel on day 4 of each cycle. Dose-limiting toxicity (DLT) definitions included grade 3-4 hematologic toxicities and grade 2-4 hand-foot syndrome, neuropathy, or diarrhea.


RESULTS
Fifteen patients were enrolled across two dose levels. Final MTD was established at nab-paclitaxel 100 mg/m(2), gemcitabine 750 mg/m(2), and capecitabine 750 mg/m(2) twice daily. Patients received a median of four treatment cycles (range 1-16). The most frequent adverse events (any grade) for the entire study cohort included fatigue, rash/hand-foot syndrome, nausea/vomiting, diarrhea, neuropathy, and elevated liver function tests. Ten patients (66.7 %) experienced at least one grade 3-4 adverse event. Grade 3-4 hematologic toxicities were uncommon. Two of 14 evaluable patients (14.3 %) exhibited a partial response, and 6 of 12 patients (50 %) with elevated CA19-9 at baseline had a ≥50 % biomarker decline.


CONCLUSIONS
While well tolerated overall, this regimen demonstrated only modest antitumor activity in patients with metastatic pancreatic cancer. Recognizing the limits of cross-study comparisons and small sample size, these results do not match those reported at MTD in the phase I/II trial of gemcitabine/nab-paclitaxel. The lower doses used in the current study suggest that dose intensity may be a critical aspect to optimize multidrug regimens.
Helen Diller Family Comprehensive Cancer Center, University of California San Francisco, 94115, USA. andrewko@medicine.ucsf.edu
Andrew H
AH
Ko
Thach-Giao
TG
Truong
Emily
E
Kantoff
Kimberly A
KA
Jones
Elizabeth
E
Dito
Anna
A
Ong
Margaret A
MA
Tempero
D000230:Adenocarcinoma / Q000097:blood / Q000188:drug therapy* / Q000473:pathology; D000368:Aged; D000068196:Albumin-Bound Paclitaxel; D000418:Albumins / Q000008:administration & dosage / Q000009:adverse effects; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage* / Q000009:adverse effects*; D014408:Biomarkers, Tumor / Q000097:blood; D018395:CA-19-9 Antigen / Q000097:blood; D000069287:Capecitabine; D003841:Deoxycytidine / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives; D018450:Disease Progression; D004334:Drug Administration Schedule; D005260:Female; D005472:Fluorouracil / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives; D006801:Humans; D053208:Kaplan-Meier Estimate; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D017239:Paclitaxel / Q000008:administration & dosage / Q000009:adverse effects; D010190:Pancreatic Neoplasms / Q000097:blood / Q000188:drug therapy* / Q000473:pathology; D016896:Treatment Outcome; D000093542:Gemcitabine
D000068196:Albumin-Bound Paclitaxel; D000418:Albumins; D014408:Biomarkers, Tumor; D018395:CA-19-9 Antigen; D003841:Deoxycytidine; D000069287:Capecitabine; D017239:Paclitaxel; D005472:Fluorouracil; D000093542:Gemcitabine