Bevacizumab plus gemcitabine and oxaliplatin as first-line therapy for metastatic or locally advanced pancreatic cancer: a phase II trial

Fogelman, David R.; Jafari, Mehrdad; Varadhachary, Gauri R.; Xiong, Henry Q.; Bullock, S.; Ozer, H.; Lin, Edward H.; Morris, Jeffrey S.; Cunningham, P; Bennett, Bronwyn; Abbruzzese, James L.; Wolff, Robert A.

doi:10.1007/s00280-011-1601-4

Cited by 23 publications

(19 citation statements)

References 22 publications

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“…16,17,19,20 Trials were conducted between 2004 and 2008 and all included patients with APCA. All studies included bevacizumab at an equivalent dose of 5 mg/kg/wk in combination with a gemcitabine doublet.…”

Section: Resultsmentioning

confidence: 99%

“…In 2 studies, the doublet contained a fluoropyrimidine, 16,20 and in 2 studies the doublet contained a platinum. 17,19 Only 2 of these trials met their primary endpoint. Median age and CA19-9 were similar among studies.…”

Section: Resultsmentioning

confidence: 99%

“…CTCAE grading was predetermined according to respective CTCAE versions used in each individual trial. Three of the 4 studies 16,17,20 used CTCAE version 3.0, and 1 study 19 used version 2.0. Clinical outcome measures including overall response rate (ORR), disease control rate (DCR) (DCR = ORR + SD > 16 wk), time to progression (TTP), and overall survival (OS) were collected for all patients.…”

Section: Methodsmentioning

confidence: 99%

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Treatment-related Hypertension as a Pharmacodynamic Biomarker for the Efficacy of Bevacizumab in Advanced Pancreas Cancer

Pant

Martin

Geyer

et al. 2016

American Journal of Clinical Oncology

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Purpose Phase III studies of bevacizumab in advanced pancreas cancer (APCA) demonstrated no improvement in outcome. No validated biomarkers for bevacizumab efficacy exist. We evaluated bevacizumab-related hypertension (B-HTN) as a biomarker in APCA patients in a pooled analysis from 4 prospective clinical trials of gemcitabine-based therapy combined with bevacizumab. Materials and Methods Data were collected from individual databases from 4 prospective, single-arm phase II trials. Patients were grouped according to B-HTN or no hypertension (HTN), and patients with HTN were further grouped according to highest Common Terminology Criteria for Adverse Events grade of HTN: grade 1-2 or grade 3-4. Clinical outcomes of overall survival, time to progression, overall response rate (ORR), and disease control rate (ORR + SD > 16 wk) were compared. Results A total of 163 patients with stage IV APCA and Eastern Cooperative Oncology Group 0-1 were included. Median age was 59 years (range, 33 to 85 y). Thirty-four patients had B-HTN, and 129 patients had no HTN. Prognostic factors were balanced between groups. Patients with any grade B-HTN had a significantly improved median overall survival (13.1 vs. 8.1 mo, P = 0.0006), median time to tumor progression (7.6 vs. 5.5 mo, P = 0.0074), ORR (47% vs. 16%, P = 0.0001), and disease control rate (85% vs. 59%, P = 0.004). There were no differences in outcomes according to HTN grade (1-2 [N = 16] vs. 3-4 [N = 18]). Conclusions APCA patients who develop any grade of B-HTN appear to derive benefit from bevacizumab. Additional investigation is needed to identify subgroups of patients who develop B-HTN and are more likely to benefit from bevacizumab.

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

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Treatment-related Hypertension as a Pharmacodynamic Biomarker for the Efficacy of Bevacizumab in Advanced Pancreas Cancer

Pant

Martin

Geyer

et al. 2016

American Journal of Clinical Oncology

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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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“…Trials involving bevacizumab as a second-line therapy option have also failed to show much promise 48, 49 . More recently, bevacizumab has been tested in combination with gemcitabine and other chemotherapies and radiation therapies in adjuvant settings and has continued to show no success 50-52 .…”

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 plus gemcitabine and oxaliplatin as first-line therapy for metastatic or locally advanced pancreatic cancer: a phase II trial

Abstract: The GEMOX/bevacizumab regimen demonstrated an excellent median overall survival but did not meet our objective of a 14 month median survival. Toxicity was significant. We do not recommend further evaluation of this regimen.

Cited by 23 publications

References 22 publications

Treatment-related Hypertension as a Pharmacodynamic Biomarker for the Efficacy of Bevacizumab in Advanced Pancreas Cancer

Treatment-related Hypertension as a Pharmacodynamic Biomarker for the Efficacy of Bevacizumab in Advanced Pancreas 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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