Originally published as JCO Early Release 10.1200/JCO.2008.21.5384 on October 26 2009

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Dose Finding and Early Efficacy Study of Gemcitabine Plus Capecitabine in Combination With Bevacizumab Plus Erlotinib in Advanced Pancreatic Cancer

From the Departments of Medicine, Radiology, and Computing and Statistics, Royal Marsden Hospital, National Health Service Foundation Trust, Surrey and London, United Kingdom.

Corresponding author: David Cunningham, MD, FRCP, Department of Medicine, Royal Marsden Hospital, Downs Rd, Sutton, Surrey, SM2 5PT, United Kingdom; e-mail: david.cunningham{at}rmh.nhs.uk.

Purpose This study evaluated safety and efficacy of chemotherapy (gemcitabine plus capecitabine) plus bevacizumab/erlotinib in advanced pancreatic cancer because dual epidermal growth factor receptor/vascular endothelial growth factor blockade has a rational biologic basis in this malignancy.

Patients and Methods Patients with untreated, unresectable, locally advanced or metastatic pancreatic carcinoma were enrolled onto one of the following four sequential dose levels (DLs) of escalating capecitabine doses (days 1 to 21): DL1, 910 mg/m²; DL2, 1,160 mg/m²; DL3, 1,400 mg/m²; or DL4, 1,660 mg/m². Doses of coadministered gemcitabine (1,000 mg/m² on days 1, 8, and 15), bevacizumab (5 mg/kg on days 1 and 15), and erlotinib (100 mg/d) every 28 days (up to six cycles) were fixed. Using a 3+3 study design, dose-limiting toxicity (DLT) was assessed in cycle 1.

Results Twenty assessable patients were enrolled (DL1, n = 8; DL2, n = 3; DL3, n = 6; and DL4, n = 3); 97 cycles were administered. Median age was 63 years (range, 33 to 77 years), and male-to-female ratio was 10:10. Performance status was 0 and 1 in two and 17 patients, respectively; and nine and 11 patients had locally advanced and metastatic disease, respectively. DLT occurred in one patient at DL1 (grade 3 epistaxis) and two patients at DL4 (grade 3 diarrhea and grade 3 skin rash > 7 days). Common grade 3 and 4 toxicities (10% to 20%) were diarrhea, hand-foot syndrome, stomatitis, and skin rash. Grade 3 lethargy and grade 3 or 4 neutropenia occurred in 40% and 45% of patients, respectively. No GI perforation, grade 3 GI hemorrhage/hypertension, or pneumonitis occurred. Ten partial responses were observed. Median overall and progression-survival times (all patients) were 12.5 and 9.0 months, respectively.

Conclusion The maximum-tolerated dose of capecitabine was 1,660 mg/m². The recommended capecitabine dose in this cytotoxic doublet/biologic doublet regimen is 1,440 mg/m²; this regimen is under evaluation in an ongoing phase II study.

See accompanying editorial on page 5487 and articles on pages 5506, 5513, and 5660

Supported by Royal Marsden Hospital National Health Service (NHS) Foundation Trust. We acknowledge NHS funding to the National Institute for Health Research Biomedical Research Centre. Hoffman-La Roche provided an educational grant toward running the trial and provided capecitabine, erlotinib, and bevacizumab at no cost.

Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.

Clinical trial information can be found for the following: NCT00260364 [ClinicalTrials.gov] .

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				J. Tabernero and T. Macarulla Changing the Paradigm in Conducting Randomized Clinical Studies in Advanced Pancreatic Cancer: An Opportunity for Better Clinical Development J. Clin. Oncol., November 20, 2009; 27(33): 5487 - 5491. [Full Text] [PDF]