John C. Brady

A Phase II Study of Capecitabine, Oxaliplatin, and Bevacizumab in the Treatment of Metastatic Esophagogastric Adenocarcinomas

BACKGROUND Esophageal and gastric cancers often present at an advanced stage. Systemic chemotherapy is the mainstay of treatment, but survival with current regimens remains poor. We evaluated the safety, tolerability, and efficacy of the combination capecitabine, oxaliplatin, and bevacizumab in the treatment of metastatic esophagogastric adenocarcinomas. METHODS Thirty-seven patients with metastatic or unresectable gastric/gastroesophageal junction tumors were enrolled and treated with capecitabine 850 mg/m(2) BID on days 1-14, and oxaliplatin 130 mg/m(2) with bevacizumab 15 mg/kg on day 1 of a 21-day cycle. The primary endpoint was progression-free survival (PFS). Secondary endpoints included response rate (RR) and overall survival (OS). Neuropilin-1 (NRP1) and -2 (NRP2) mRNA expression was evaluated in archived tumor. RESULTS Thirty-five patients were evaluable for efficacy. Median PFS was 7.2 months; median OS was 10.8 months. RR was estimated at 51.4%. The regimen was tolerable with expected drug class-related toxicities. NRP2 mRNA levels significantly correlated with PFS (p = 0.042) and showed a trend toward significance with OS (p = 0.051). Nonsignificant trends for NRP1 were noted for higher expression levels and worse outcome. CONCLUSIONS Bevacizumab can be given safely with chemotherapy in patients with metastatic esophagogastric adenocarcinomas. The combination of capecitabine, oxaliplatin, plus bevacizumab has activity comparable to other bevacizumab-containing regimens in metastatic gastroesophageal cancer.

Modulation of circulating protein biomarkers following TRC105 (anti-endoglin antibody) treatment in patients with advanced cancer

TRC105 is an endoglin‐targeting drug that possesses anti‐angiogenic and antitumor potential. Analysis of the initial phase I trial of TRC105 demonstrated good tolerability and efficacy in cancer patients. In this report, we analyzed multiple circulating biomarkers at baseline, cycle 2 day 1 (C2D1), and end of study (EOS) for each patient. The baseline level and the fold change from baseline to both C2D1 and EOS for each marker were statistically analyzed. At C2D1, seven markers were significantly downregulated (angiopoietin‐2 [Ang‐2], insulin‐like growth factor‐binding protein‐3 [IGFBP‐3], plasminogen activator inhibitor‐1 [PAI‐1] total, platelet‐derived growth factor [PDGF]‐AA, PDGF‐BB, thrombospondin‐1 [TSP‐1], and vascular endothelial growth factor [VEGF]‐D). Meanwhile, seven markers were upregulated by C2D1 (E‐Cadherin, soluble Endoglin [sEnd], E‐Selectin, interleukin‐6 [IL‐6], osteopontin [OPN], TSP‐2, and von Willebrand factor [vWF]). At EOS, seven markers were upregulated including Ang‐2, C‐reactive protein (CRP), intercellular adhesion molecule‐1 (ICAM‐1), IGFBP‐1, IL‐6, TSP‐2, and vascular cell adhesion molecule‐1 (VCAM‐1). A statistical trend was also seen for increases of VEGF‐A and placenta growth factor (PlGF) at EOS. Throughout treatment, sEnd levels significantly increased, an observation that was recapitulated in cultured endothelial cells. This is the first report of plasma‐based biomarkers in patients receiving TRC105. TRC105 treatment by C2D1 was associated with decreases in several angiogenic factors, including Ang‐2, PDGF isoforms, and VEGF isoforms, offering insight into the mechanisms underlying TRC105s anti‐angiogenic, antitumor function. Increases in sEnd were the most significant of all observed biomarker changes and may reflect direct drug effects. Additionally, biomarker changes in response to TRC105 are distinct from those seen in patients treated with VEGF‐targeting drugs, suggesting the possible utility of combining these two classes of angiogenesis inhibitors in patients.

Biomarker Signatures Correlate with Clinical Outcome in Refractory Metastatic Colorectal Cancer Patients Receiving Bevacizumab and Everolimus

A novel combination of bevacizumab and everolimus was evaluated in refractory colorectal cancer patients in a phase II trial. In this retrospective analysis, plasma samples from 49 patients were tested for over 40 biomarkers at baseline and after one or two cycles of drug administration. Analyte levels at baseline and change on-treatment were correlated with progression-free survival (PFS) and overall survival (OS) using univariate Cox proportional hazard modeling. Multivariable analyses were conducted using Cox modeling. Significant changes in multiple markers were observed following bevacizumab and everolimus treatment. Baseline levels of six markers significantly correlated with PFS and OS, including CRP, Gro-α, IGFBP-1, TF, ICAM-1, and TSP-2 (P < 0.05). At C2D1, changes of IGFBP-3, TGFβ-R3, and IGFBP-2 correlated with PFS and OS. Prognostic models were developed for OS and PFS (P = 0.0002 and 0.004, respectively). The baseline model for OS consisted of CRP, Gro-α, and TF, while the on-treatment model at C2D1 included IGFBP-2, IGFBP-3, and TGFβ-R3. These data demonstrated that multiple biomarkers were significantly modulated in response to bevacizumab and everolimus. Several markers correlated with both PFS and OS. Interestingly, these markers are known to be associated with inflammation and IGF signaling, key modulators of mTOR biology. Mol Cancer Ther; 14(4); 1048–56. ©2015 AACR.

Pilot Evaluation of Angiogenesis Signaling Factor Response after Transcatheter Arterial Embolization for Hepatocellular Carcinoma

Purpose To identify changes in a broad panel of circulating angiogenesis factors after bland transcatheter arterial embolization (TAE), a purely ischemic treatment for hepatocellular carcinoma (HCC). Materials and Methods This prospective HIPAA-compliant study was approved by the institutional review board. Informed written consent was obtained from all participants prior to entry into the study. Twenty-five patients (21 men; mean age, 61 years; range, 30-81 years) with Liver Imaging Reporting and Data System category 5 or biopsy-proven HCC and who were undergoing TAE were enrolled from October 15, 2014, through December 2, 2015. Nineteen plasma angiogenesis factors (angiopoietin 2; hepatocyte growth factor; platelet-derived growth factor AA and BB; placental growth factor; vascular endothelial growth factor A and D; vascular endothelial growth factor receptor 1, 2, and 3; osteopontin; transforming growth factor β1 and β2; thrombospondin 2; intercellular adhesion molecule 1; interleukin 6 [IL-6]; stromal cell-derived factor 1; tissue inhibitor of metalloproteinases 1; and vascular cell adhesion molecule 1 [VCAM-1]) were measured by using enzyme-linked immunosorbent assays at 1 day, 2 weeks, and 5 weeks after TAE and were compared with baseline levels by using paired Wilcoxon tests. Tumor response was assessed according to modified Response Evaluation Criteria in Solid Tumors (mRECIST). Angiogenesis factor levels were compared between responders and nonresponders by mRECIST criteria by using unpaired Wilcoxon tests. Results All procedures were technically successful with no complications. Fourteen angiogenesis factors showed statistically significant changes following TAE, but most changes were transient. IL-6 was upregulated only 1 day after the procedure, but showed the largest increases of any factor. Osteopontin and VCAM-1 demonstrated sustained upregulation at all time points following TAE. At 3-month follow-up imaging, 11 patients had responses to TAE (complete response, n = 6; partial response, n = 5) and 11 patients were nonresponders (stable disease, n = 9; progressive disease, n = 2). In nonresponders, the percent change in IL-6 on the day after TAE (P = .033) and the mean percent change in osteopontin after TAE (P = .024) were significantly greater compared with those of responders. Conclusion Multiple angiogenesis factors demonstrated significant upregulation after TAE. VCAM-1 and osteopontin demonstrated sustained upregulation, whereas the rest were transient. IL-6 and osteopontin correlated significantly with radiologic response after TAE.

Modulation of Circulating Protein Biomarkers in Cancer Patients Receiving Bevacizumab and the Anti-Endoglin Antibody, TRC105

TRC105 is an anti-endoglin antibody currently being tested in combination with VEGF inhibitors. In the phase Ib trial, 38 patients were treated with both TRC105 and bevacizumab (BEV), and improved clinical outcomes were observed, despite the fact that 30 patients (79%) were refractory to prior anti-VEGF therapy. Plasma samples were tested for angiogenic and inflammatory biomarkers at baseline and on-treatment. To provide broader context of this combination biomarker study, direct cross-study comparisons were made to biomarker studies previously conducted in patients treated with either BEV or TRC105 monotherapy. Upon treatment with BEV and TRC105, pharmacodynamic changes in response to both BEV (PlGF increase) and TRC105 (soluble endoglin increase) were noted. In addition, distinct patterns of change were identified (similar, opposing, neutralizing). Similar patterns were observed when the combination elicited similar effects to those observed with monotherapy treatment (i.e., decreases of Ang-2, increases of IL6 and VCAM-1). Opposing patterns were observed when the combination led to opposing effects compared with monotherapy treatment (i.e., TGFβ1, PDGF-AA and PDGF-BB, PAI-1). Lastly, neutralizing patterns were observed when one drug led to increase, whereas the other drug led to decrease, and the combination elicited no overall effect on the marker (i.e., VEGF-A, VEGF-D, and IGFBP-3). Patients achieving partial responses or stable disease from the combination exhibited significantly lower expression of E-Cadherin, HGF, ICAM-1, and TSP-2 at baseline. Taken together, the novel biomarker modulations identified may deepen our understanding of the underlying biology in patients treated with BEV and TRC105 compared with either drug alone. Mol Cancer Ther; 17(10); 2248–56. ©2018 AACR.