Cediranib in patients with malignant mesothelioma: A phase II trial of the University of Chicago Phase II Consortium

Campbell, Nicholas; Kunnavakkam, Rangesh; Leighl, Natasha B.; Vincent, Mark; Gandara, David R.; Koczywas, Marianna; Gitlitz, Barbara J.; Agamah, Edem; Thomas, Sachdev; Stadler, Walter M.; Vokes, Everett E.; Kindler, Hedy L.

doi:10.1016/j.lungcan.2012.06.011

Cited by 49 publications

(31 citation statements)

References 25 publications

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“…Angiogenesis is a complex process, difficult to target due to multiple VEGF-dependent and VEGF-independent pathways 35,36. Multiple antiangiogenic agents have been previously used for the treatment of MPM; however, responses have been modest with bevacizumab having the most evidence 37–47. A recent publication reporting the combination of bevacizumab with pemetrexed and cisplatin showed increased PFS and OS 41.…”

Section: Discussionmentioning

confidence: 99%

A pilot study of zoledronic acid in the treatment of patients with advanced malignant pleural mesothelioma

Jamil¹,

Jerome²,

Miley³

et al. 2017

LCTT

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PurposeMalignant pleural mesothelioma (MPM) is a rare malignancy with a dismal median survival of <12 months with current therapy. Single and combination chemotherapy regimens have shown only modest clinical benefit. In preclinical studies, nitrogen-containing bisphosphonates (zoledronic acid) inhibit growth of mesothelioma cells by different mechanisms: inhibition of mevalonate pathway, inhibition of angiogenesis, activation of apoptosis through caspase activation, and alteration in activity of matrix metalloproteinases, thereby affecting invasiveness of cancer cells.Patients and methodsWe investigated the role of zoledronic acid in a pilot, single-arm trial of MPM patients with Eastern Cooperative Oncology Group (ECOG) performance status (PS) 0–2 who had progressed on prior treatments or had not received systemic therapy due to poor PS. Primary end point was composite response rate by modified response evaluation criteria in solid tumors and/or metabolic response by 2-deoxy-2-[fluorine-18]fluoro-d-glucose (18F-FDG) positron emission tomography criteria. Secondary end points were progression-free survival (PFS) and overall survival (OS). Exploratory end points include the effect of zoledronic acid therapy on vascular endothelial growth factor (VEGF), basic fibroblast growth factor, interleukin 8, transforming growth factor beta, mesothelin, and osteopontin levels.ResultsEight male patients (median age of 62 years) with the following clinical characteristics were treated; ECOG PS was 0–2, 75% with epithelioid type, and 62% had prior chemotherapy Overall composite response rate was 12.5% and the clinical benefit rate (response + stable disease) was 37.5%. Median PFS was 2 months (0.5–21 months) and median OS was 7 months (0.8–28 months). No treatment-related toxicities were observed. Lower VEGF levels were predictive of favorable response and mesothelin levels correlated with disease course.ConclusionZoledronic acid shows modest clinical activity without significant toxicity in patients with advanced MPM.

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Section: Discussionmentioning

confidence: 99%

A pilot study of zoledronic acid in the treatment of patients with advanced malignant pleural mesothelioma

Jamil¹,

Jerome²,

Miley³

et al. 2017

LCTT

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“…Cediranib is a potent small molecule inhibitor of VEGFR1-3, c-Kit, and PDGFR-β signaling (76,77). Patients with MPM who had previously been treated with platinum containing therapy demonstrated a 9-10% response rate to therapy with cediranib 45 mg po daily (78,79). Tsao et al reported the phase I portion of the SWOG 0905 evaluating cediranib combined with standard of care platinum and pemetrexed therapy followed by cediranib maintenance therapy in chemotherapy naive patients with unresectable MPM (80).…”

Section: Anti-angiogenic Therapymentioning

confidence: 99%

Novel systemic therapy against malignant pleural mesothelioma

Mancuso

Neal

2017

Transl. Lung Cancer Res.

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Malignant pleural mesothelioma is an aggressive tumor of the pleura with an overall poor prognosis. Even with surgical resection, for which only a subset of patients are eligible, long term disease free survival is rare. Standard first-line systemic treatment consists of a platinum analog, an anti-metabolite, and sometimes anti-angiogenic therapy, but there is currently no well-established standard therapy for refractory or relapsed disease. This review focuses on efforts to develop improved systemic therapy for the treatment of malignant pleural mesothelioma (MPM) including cytotoxic systemic therapy, a variety of tyrosine kinase inhibitors and their downstream effector pathways, pharmacologic targeting of the epigenome, novel approaches to target proteins expressed on mesothelioma cells (such as mesothelin), arginine depletion therapy, and the emerging role of immunotherapy. Overall, these studies demonstrate the challenges of improving systemic therapy for MPM and highlight the need to develop therapeutic strategies to control this disease.

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“…These results might translate into addition of bevacizumab as part of the first line treatment for MPM. A specific RTK inhibitor targeting all three isoforms of VEGF receptors (VEGFRs) 1–3, cediranib, also showed only modest activity in unselected MM patients [109,110]. Moreover, other RTK inhibitors targeting VEGFRs and multiple other receptors, such as sunitinib, sorafenib and valatanib, also showed very limited activity in MM [111–116].…”

Section: Molecular Genetics and Molecular Therapiesmentioning

confidence: 99%

Latest developments in our understanding of the pathogenesis of mesothelioma and the design of targeted therapies

Bononi

Napolitano

Pass

et al. 2015

Expert Review of Respiratory Medicine

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Malignant mesothelioma is an aggressive cancer whose pathogenesis is causally linked to occupational exposure to asbestos. Familial clusters of mesotheliomas have been observed in settings of genetic predisposition. Mesothelioma incidence is anticipated to increase worldwide in the next two decades. Novel treatments are needed, as current treatment modalities may improve the quality of life, but have shown modest effects in improving overall survival. Increasing knowledge on the molecular characteristics of mesothelioma has led to the development of novel potential therapeutic strategies, including: (i) molecular targeted approaches, i.e. the inhibiton of vascular endothelial growth factor with Bevacizumab; (ii) immunotherapy with chimeric monoclonal antibody, immunotoxin, antibody drug conjugate, vaccine and viruses; (iii) inhibition of asbestos-induced inflammation, i.e. aspirin inhibition of HMGB1 activity may decrease or delay mesothelioma onset and/or growth. We elaborate on the rationale behind new therapeutic strategies, and summarize available preclinical and clinical results, as well as efforts still ongoing.

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Cediranib in patients with malignant mesothelioma: A phase II trial of the University of Chicago Phase II Consortium

Cited by 49 publications

References 25 publications

A pilot study of zoledronic acid in the treatment of patients with advanced malignant pleural mesothelioma

A pilot study of zoledronic acid in the treatment of patients with advanced malignant pleural mesothelioma

Novel systemic therapy against malignant pleural mesothelioma

Latest developments in our understanding of the pathogenesis of mesothelioma and the design of targeted therapies

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