SWOG S0727: A randomized phase II trial of combination gemcitabine plus erlotinib plus IMC-A12 (cixutumumab) versus gemcitabine plus erlotinib as first-line treatment in patients (pts) with metastatic pancreatic cancer.

Philip, P. A.; Ramanathan, Ramesh K.; Lowy, A. M.; Whitehead, Robert P.; Iqbal, Syma; Chung, Vincent; Benedetti, Jacqueline; Blanke, Charles D.

doi:10.1200/jco.2010.28.15_suppl.tps223

Cited by 4 publications

(4 citation statements)

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“…Philip et al presented data of a phase I trial on cixutumumab (IMC-A12, Eli Lilly and Company, Indianapolis, IN), which was added to the standard regimen of gemcitabine and erlotinib (an EGFR tyrosine kinase inhibitor), at the ASCO 2010 Fig. The combination of these three substances was well tolerated and a phase II trial on these substances is currently being conducted [30]. The receptor tyrosine kinases IGF-1R, EGFR (epidermal growth factor receptor), PDGFR (platelet-derived growth factor receptors), and VEGFR (vascular endothelial growth factor receptor) activate the MAPK/ERK pathway and the PI3K/Akt pathway.…”

Section: Monoclonal Antibodies Blocking Igf-1rmentioning

confidence: 99%

Insulin-Like Growth Factor Signaling as a Therapeutic Target in Pancreatic Cancer

Rieder

Michalski²,

Friess³

et al. 2011

ACAMC

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Insulin-like growth factor-1 (IGF-1) leads via its receptor IGF-1R to the activation of the PI3K/Akt pathway, providing antiapoptotic signals to pre-malignant and malignant cells. In pancreatic cancer, IGF-1 and its receptor are constitutively overexpressed. Mammalian target of rapamycin (mTOR) is the main mediator of mitogenic stimuli transduced by PI3K/Akt. Interestingly, inhibition of mTOR activates PI3K/Akt by up-regulating IGF-1R signaling. Several targeted agents have been developed to inhibit the activity of IGF-1 or to block IGF-1R. These pharmaceuticals may offer additional ways of stimulating apoptosis in neoplastic cells. Yet, there are difficulties in targeting this pathway: The ideal anti-cancer drug target is expressed only in cancer cells; however, IGF-1 and its receptor IGF-1R are ubiquitously expressed throughout the body. Moreover, when using antibodies against IGF-1R, the structurally similar insulin receptor might also be blocked, leading to hyperglycemia as a severe side effect. There are currently several phase I/II trials investigating IGF-1 and its receptor as a drug target in various kinds of cancer. Specifically, therapeutic effects on pancreatic cancer by combining a humanized monoclonal antibody against IGF-1R with other chemotherapeutics are being investigated. To improve the clinical outcome of mTOR inhibitors such as everolimus, it has been suggested to use combination therapies of mTOR inhibitors and IGF-1/IGF-1R inhibitors. In theory, this would counterbalance the feedback effects of mTOR inhibition on IGF-1 signaling. In conclusion, IGF-1 and its receptor are promising new drug targets in cancer therapy. Combination therapies of IGF-1/IGF-1R inhibitors and mTOR inhibitors could improve the clinical outcome.

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Section: Monoclonal Antibodies Blocking Igf-1rmentioning

confidence: 99%

Insulin-Like Growth Factor Signaling as a Therapeutic Target in Pancreatic Cancer

Rieder

Michalski²,

Friess³

et al. 2011

ACAMC

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“…Early phase I trial evaluating the triplet combination of gemcitabine, erlotinib, and cixutumumab showed no excessive toxicity, and the regimen was carried to a randomized phase II trial in APC (SWOG-S0727) [51]. Preliminary results were negative.…”

Section: Future Perspectivesmentioning

confidence: 99%

Advanced Pancreatic Cancer: Flourishing Novel Approaches in the Era of Biological Therapy

Chiu¹,

Wong²,

Leung³

et al. 2014

The Oncologist

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The progress in the development of systemic treatment for advanced pancreatic cancer (APC) has been slow. The mainstream treatment remains using chemotherapy including gemcitabine, FOLFIRINOX, and nab-paclitaxel. Erlotinib is the only approved biological therapy with marginal benefit. Studies of agents targeting epidermal growth factor receptor, angiogenesis, and RAS signaling have not been satisfying, and the usefulness of targeted therapy in APC is uncertain. Understanding in molecular processes and tumor biology has opened the door for new treatment strategies such as targeting insulin-like growth factor 1 receptor, transforming growth factor b, phosphoinositide 3-kinase/AKT/mammalian target of rapamycin pathway, and Notch pathway. New directions also include the upcoming immunotherapy and many novel agents that act on the microenvironment. The practice of personalized medicine using predictive biomarkers and pharmacogenomics signatures may also enhance the effectiveness of existing treatment. Future treatment approaches may involve comprehensive genomic assessment of tumor and integrated combinations of multiple agents to overcome treatment resistance. The Oncologist 2014;19:937-950 Implications for Practice: Pancreatic cancer is a dismal disease with an unmet need for novel treatment approaches. This paper provides a comprehensive review in the current development of new treatment strategies, supported with concise scientific background and brief descriptions of ongoing phase II/III clinical trials. It provides both nonspecialists and specialists in pancreatic cancer care an overview of the topic that they can easily reference in their clinical practice or research.

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“…Morgan et al reported cetuximab together with gemcitabine and radiation effectively prolonged pancreatic cancer xenograft volume doubling time, and produced a synergistic effect with gemcitabine and radiation [18]. However, an enhanced antitumor effect was not observed in pancreatic cancer clinical trials with cetuximab combined with gemcitabine, or gemcitabine/cisplatin [19–21]. In a phase III study of gemcitabine plus cetuximab vs. gemcitabine alone the median survival was 6.3 months with progression-free survival of 3.4 months in the combination treatment group, vs. 5.9 months and 3 months respectively in the gemcitabine group [20].…”

Section: Introductionmentioning

confidence: 99%

“…Additive effects were observed when IMC-A12 was combined with cetuximab and gemcitabine in pancreatic cancer xenograft models [59]. Combination therapy using this antibody together with gemcitabine and erlotinib is in a phase II clinical trial of pancreatic cancer patients [21]. …”

Section: Introductionmentioning

confidence: 99%

Molecular Targeted Approaches for Treatment of Pancreatic Cancer

Huang¹,

Saluja²,

Dudeja³

et al. 2011

CPD

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Human pancreatic cancer remains a highly malignant disease with almost similar incidence and mortality despite extensive research. Many targeted therapies are under development. However, clinical investigation showed that single targeted therapies and most combined therapies were not able to improve the prognosis of this disease, even though some of these therapies had excellent anti-tumor effects in pre-clinical models. Cross-talk between cell proliferation signaling pathways may be an important phenomenon in pancreatic cancer, which may result in cancer cell survival even though some pathways are blocked by targeted therapy. Pancreatic cancer may possess different characteristics and targets in different stages of pathogenesis, maintenance and metastasis. Sensitivity to therapy may also vary for cancer cells at different stages. The unique pancreatic cancer structure with abundant stroma creates a tumor microenvironment with hypoxia and low blood perfusion rate, which prevents drug delivery to cancer cells. In this review, the most commonly investigated targeted therapies in pancreatic cancer treatment are discussed. However, how to combine these targeted therapies and/or combine them with chemotherapy to improve the survival rate of pancreatic cancer is still a challenge. Genomic and proteomic studies using pancreatic cancer samples obtained from either biopsy or surgery are recommended to individualize tumor characters and to perform drug sensitivity study in order to design a tailored therapy with minimal side effects. These studies may help to further investigate tumor pathogenesis, maintenance and metastasis to create cellular expression profiles at different stages. Integration of the information obtained needs to be performed from multiple levels and dimensions in order to develop a successful targeted therapy.

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SWOG S0727: A randomized phase II trial of combination gemcitabine plus erlotinib plus IMC-A12 (cixutumumab) versus gemcitabine plus erlotinib as first-line treatment in patients (pts) with metastatic pancreatic cancer.

Cited by 4 publications

References 0 publications

Insulin-Like Growth Factor Signaling as a Therapeutic Target in Pancreatic Cancer

Insulin-Like Growth Factor Signaling as a Therapeutic Target in Pancreatic Cancer

Advanced Pancreatic Cancer: Flourishing Novel Approaches in the Era of Biological Therapy

Molecular Targeted Approaches for Treatment of Pancreatic Cancer

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