Bevacizumab combined with gemcitabine and capecitabine for advanced pancreatic cancer: a phase II study

Javle, Milind; Yu, Jihnhee; Garrett, Christopher R.; Pande, A. U.; Kuvshinoff, Boris W.; Litwin, Alan; Phelan, John T.; Gibbs, John F.; Iyer, Renuka

doi:10.1038/sj.bjc.6605099

Cited by 33 publications

(24 citation statements)

References 23 publications

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“…Several Phase I and II studies demonstrated relatively longer overall median survival of 11 and 12 mo. 39,40,50,52 These studies did not include a control group, had relative small sample size and lack randomization. These results were probably affected by a relative early clinical stage that enabled in part surgical resection 40 and the possible additive contribution of radiation.…”

Section: Summary and Future Directionsmentioning

confidence: 97%

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Kinase signaling pathways as targets for intervention in pancreatic cancer

Preis

Korc²

2010

Cancer Biology & Therapy

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Pancreatic ductal adenocarcinoma (PDAC) is the fourth leading cause of cancer related mortality in the United States. The prognosis of patients with PDAC is extremely poor with a median survival of 6 months, in part due to the advanced stage at the time of diagnosis and early metastatic spread. A considerable body of evidence points to the involvement of the tyrosine kinase and serine/threonine kinase pathways as major effectors in pancreatic cancer development and as potential targets for intervention. These pathways regulate multiple cellular processes including cell growth, proliferation, migration, invasion and resistance to apoptosis. The relatively recent introduction of novel therapies targeting tyrosine kinase and serine/threonine kinase pathways have yielded dramatic results in certain hematological malignancies, and have resulted in significant advances in our ability to treat patients with melanoma, breast, lung and colon cancer, thereby leading to improved survival and quality of life. Unfortunately, similar therapeutic improvements have not occurred in PDAC. Thus, despite encouraging phase I/II studies, the vast majority of phase-III studies have failed to demonstrate improved efficacy in PDAC. This review will provide an overview on the different kinase signaling pathways in PDAC and the supporting data on targeted therapies available from pre-clinical and clinical studies.

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Section: Summary and Future Directionsmentioning

confidence: 97%

“…49 Phase II studies in PDAC designed to test safety and efficacy yielded promising results. [50][51][52] However, three randomized Phase III studies demonstrated mildly improved progression free survival (PFS) but no improvement in overall survival ( Table 2). [53][54][55] Small molecule inhibitors.…”

Section: Receptor Tyrosine Kinasesmentioning

confidence: 98%

Kinase signaling pathways as targets for intervention in pancreatic cancer

Preis

Korc²

2010

Cancer Biology & Therapy

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“…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].…”

Section: Clinical Studies In Pdacmentioning

confidence: 99%

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

2016

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The importance of angiogenesis in Pancreatic Ductal Adenocarcinoma (PDAC) and its therapeutic potential have been explored in both pre-clinical and clinical studies. Human PDACs overexpress a number of angiogenic factors and their cognate high-affinity receptors, and anti-angiogenic agents reduce tumor volume, metastasis, and microvessel density (MVD), and improve survival in subcutaneous and orthotopic pre-clinical models. Nonetheless, clinical trials using anti-angiogenic therapy have been overwhelmingly unsuccessful. This review will focus on these pre-clinical and clinical studies, the potential reasons for failure in the clinical setting, and ways these shortcomings could be addressed in future investigations of angiogenic mechanisms in PDAC.

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“…Bevacizumab is a recombinant humanized anti-human VEGF monoclonal antibody that disrupts the binding between VEGF and its ligand. Bevacizumab has been shown to have a synergistic effect in inhibiting tumor activity when combined with chemotherapies 41, 42 . A phase II trial in advanced PDA patients showed that bevacizumab in combination with gemcitabine improved the response rate and the median survival time compared to gemcitabine alone 40 .…”

Section: Current Monoclonal Antibody Therapies For Pda Treatmentmentioning

confidence: 99%

“…Along similar lines, cetuximab and bevacizumab used in combination with or without gemcitabine did not show favorable results 47 . The failed phase III studies infused doubt in the favorable results of another phase II study that combined gemcitabine, capecitabine and bevacizumab leading the investigators to not move forward to a phase III trial 42 . Trials involving bevacizumab as a second-line therapy option have also failed to show much promise 48, 49 .…”

Section: Current Monoclonal Antibody Therapies For Pda Treatmentmentioning

confidence: 99%

Specificity Delivers: Therapeutic Role of Tumor Antigen-Specific Antibodies in Pancreatic Cancer

Jhaveri

Jaffee

2014

Seminars in Oncology

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Pancreatic ductal adenocarcinoma (PDA) is among the most deadly cancers with less than 5% of the patients living beyond 5 years post-diagnosis. Lack of early diagnostic biomarkers and resistance to current therapies help explain these disappointing numbers. Thus, more effective and better-targeted therapies are needed quickly. Monoclonal antibodies offer an attractive alternative targeted therapy option for PDA because they are highly specific and potent. However, currently available monoclonal antibody therapies for PDA are still in its infancy with a low success rate of being approved. The challenges faced by these therapies include lack of predictive and response biomarkers, unfavorable safety profiles, expression of targets not restricted to the cancer cells, flawed preclinical model systems, drug resistance and PDA’s complex nature. Additionally, discovery of novel PDA-specific antigen targets, present on the cell surface or in the extracellular matrix, is needed. Predictive and response markers also need to be determined for PDA patient subgroups so that the most appropriate effective therapy can be delivered. Serologic approaches, recombinant antibody producing technologies and advances in antibody engineering techniques will help identify these predictive biomarkers and aid in the development of new therapeutic antibodies. A combinatorial approach simultaneously targeting antigens on the PDA cell, stroma and immunosuppressive cells should be employed.

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Bevacizumab combined with gemcitabine and capecitabine for advanced pancreatic cancer: a phase II study

Cited by 33 publications

References 23 publications

Kinase signaling pathways as targets for intervention in pancreatic cancer

Kinase signaling pathways as targets for intervention in pancreatic cancer

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

Specificity Delivers: Therapeutic Role of Tumor Antigen-Specific Antibodies in Pancreatic Cancer

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