Phase II and Coagulation Cascade Biomarker Study of Bevacizumab With or Without Docetaxel in Patients With Previously Treated Metastatic Pancreatic Adenocarcinoma

Abstract

Purpose Treatment options are limited for advanced pancreatic cancer progressive after gemcitabine therapy. The vascular endothelial growth factor (VEGF) pathway is biologically important in pancreatic cancer, and docetaxel has modest anti-tumor activity. We evaluated the role of the anti-VEGF antibody bevacizumab as second-line treatment for patients with metastatic pancreatic cancer. Design Patients with metastatic adenocarcinoma of the pancreas who had progressive disease on a gemcitabine-containing regimen were randomized to receive bevacizumab alone or bevacizumab in combination with docetaxel. Results Thirty-two patients were enrolled; 16 to bevacizumab alone (Arm A) and 16 to bevacizumab plus docetaxel (Arm B). Toxicities were greater in Arm B with the most common grade 3/4 nonhematologic toxicities including fatigue, diarrhea, dehydration and anorexia. No confirmed objective responses were observed. At 4 months, 2/16 patients in Arm A and 3/16 in Arm B were free from progression. The study was stopped according to the early stopping rule for futility. Median PFS and OS were 43 days and 165 days in Arm A and 48 days and 125 days in Arm B. Elevated D-dimer levels and thrombin-antithrombin complexes were associated with decreased survival and increased toxicity. Conclusion Bevacizumab with or without docetaxel does not have antitumor activity in gemcitabine-refractory metastatic pancreatic cancer. Baseline and on-treatment D-dimer and thrombin-antithrombin complex levels are associated with increased toxicity and decreased survival.

Phase I Safety and Pharmacokinetic Study of Bavituximab, a Chimeric Phosphatidylserine-Targeting Monoclonal Antibody, in Patients with Advanced Solid Tumors

“…The prevalence of D-dimer elevations at baseline and throughout treatment (consistent with the well-recognized association between progressive malignancy, activation of coagulation, and fibrinolysis; refs. [23][24][25][26][27][28], along with a failure to predict thromboembolic events, render this assay noninformative in this population. Accordingly, the ongoing and future studies of bavituximab do not include D-dimer eligibility requirements or monitoring.…”

Screening of Conditionally Reprogrammed Patient-Derived Carcinoma Cells Identifies ERCC3–MYC Interactions as a Target in Pancreatic Cancer

“…Treatments such as the anti-angiogenic agent bevacizumab [8], the Sonic Hedgehog (Shh) inhibitor vismodegib [9] or the EGFR receptor-targeting agent cetuximab [10] produced partial responses or limited stable disease in some individuals, but no statistically significant improvements in the general population of PDAC patients. With 30–41 new drugs granted FDA approval each year for cancer therapy [7], there has been a notable lack of progress in pancreatic cancer, with only 4 new agents becoming available to the patients in the past 20 years.…”

Overview of pre-clinical and clinical studies targeting angiogenesis in pancreatic ductal adenocarcinoma

“…These regimens included: cisplatin and gemcitabine [46]; capecitabine and gemcitabine [47]; capecitabine, radiation, and gemcitabine [48]; oxaliplatin and gemcitabine [49]; gemcitabine and radiation [50, 51], and docetaxel [52] (Table 1). However, results from the Phase III trial directly comparing bevacizumab plus gemcitabine to placebo plus gemcitabine in advanced PDAC patients showed that the addition of bevacizumab does not result in an improvement in overall survival (OS) or progression free survival (PFS) or differences in the ORR (Table 3) [53].…”

“…It would be useful if we could identify those patients who might benefit the most via the use of predictive biomarkers. Though some trials have attempted to look for correlations between certain known pro-angiogenic molecules circulating in the plasma and treatment response, none have been successful to date [44, 46, 52, 76]. With an increasing number of studies utilizing high throughput technologies like RNA sequencing (RNA-Seq) to profile human tumors, it is possible that a gene expression signature could be used.…”