A randomized, placebo-controlled phase III trial of masitinib plus gemcitabine in the treatment of advanced pancreatic cancer

Deplanque, Gaël; Demarchi, Martin; Hebbar, Mohamed; Flynn, Patrick J.; Melichar, Bohuslav; Atkins, James N.; Nowara, Elżbieta; Moyé, Lemuel A.; Piquemal, David; Ritter, Didier; Dubreuil, Patrice; Mansfield, Colin D.; Acin, Y.; Moussy, Alain; Hermine, Olivier; Hammel, Pascal

doi:10.1093/annonc/mdv133

Cited by 80 publications

(44 citation statements)

References 11 publications

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“…Based on this background, will be possible to design clinical trials with novel anti-angiogenetic therapies targeting MCs degranulation by mean of c-Kit-R tyrosine kinase inhibitors (e.g., masitinib) or inhibiting tryptase by mean of gabexate mesilate or nafamostat mesilate [58,59,60,61,62,63]. Finally, MCDPT could be evaluated as a possible predictive biomarker able to select patients candidable to novels anti-angiogenic strategies.…”

Section: Discussionmentioning

confidence: 99%

Mast Cells Density Positive to Tryptase Correlate with Microvascular Density in both Primary Gastric Cancer Tissue and Loco-Regional Lymph Node Metastases from Patients That Have Undergone Radical Surgery

Ammendola

Sacco

Zuccalà

et al. 2016

IJMS

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Mast Cells (MCs) play a role in immune responses and more recently MCs have been involved in tumoral angiogenesis. In particular MCs can release tryptase, a potent in vivo and in vitro pro-angiogenic factor via proteinase-activated receptor-2 (PAR-2) activation and mitogen-activated protein kinase (MAPK) phosphorylation. MCs can release tryptase following c-Kit receptor activation. Nevertheless, no data are available concerning the relationship among MCs Density Positive to Tryptase (MCDPT) and Microvascular Density (MVD) in both primary gastric cancer tissue and loco-regional lymph node metastases. A series of 75 GC patients with stage T2–3N2–3M0 (by AJCC for Gastric Cancer Seventh Edition) undergone to radical surgery were selected for the study. MCDPT and MVD were evaluated by immunohistochemistry and by image analysis system and results were correlated each to other in primary tumor tissue and in metastatic lymph nodes harvested. Furthermore, tissue parameters were correlated with important clinico-pathological features. A significant correlation between MCDPT and MVD was found in primary gastric cancer tissue and lymph node metastases. Pearson t-test analysis (r ranged from 0.74 to 0.79; p-value ranged from 0.001 to 0.003). These preliminary data suggest that MCDPT play a role in angiogenesis in both primary tumor and in lymph node metastases from GC. We suggest that MCs and tryptase could be further evaluated as novel targets for anti-angiogenic therapies.

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Section: Discussionmentioning

confidence: 99%

Mast Cells Density Positive to Tryptase Correlate with Microvascular Density in both Primary Gastric Cancer Tissue and Loco-Regional Lymph Node Metastases from Patients That Have Undergone Radical Surgery

Ammendola

Sacco

Zuccalà

et al. 2016

IJMS

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“…Sample size ranged from 125 to 607 patients, with a combined sample of 2,975 patients. Almost all included studies evaluated gemcitabine-based chemotherapy regimens [16][17][18][19][20][21]. Only the study from Conroy et al evaluated FOLFIRINOX [22].…”

Section: Resultsmentioning

confidence: 99%

The impact of metastatic sites in advanced pancreatic adenocarcinoma, systematic review and meta-analysis of prospective randomized studies

et al. 2020

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The real impact of specific sites of metastasis on prognosis of metastatic pancreatic cancer (MPC) is unknown. To evaluate the association of specific metastatic sites and survival outcomes in MPC a systematic literature review was performed including prospective randomized trials of systemic treatments in metastatic pancreatic cancer indexed in PubMed, Embase and Web of Science. Data regarding systemic treatment regimens, progression free survival and overall survival were extracted. The outcomes were compared using a random effects model. The index I2 and the graphs of funnel plot were used for the interpretation of the data. Of 1,052 abstracts, 7 randomized trials were considered eligible with a combined sample size of 2,975 MPC patients. Combining the studies with meta-analysis, we could see that patients with liver metastasis had a HR for death of 1.53 with 95% CI of 1.15 to 2.02 (p-value 0.003) and HR for risk of progression of 1.96 with 95% CI of 1.28 to 2.99 (p-value 0.002), without significant heterogeneity. Having two or more sites of metastasis comparing to one site did not have impact on overall survival; RR of 1.05 with 95% CI 0.91 to 1.23 (p-value 0.493). In conclusion, liver metastasis confers worse outcomes among patients with MPC. Apparently, multiple metastatic sites do not present worse prognosis when compared with only one organ involved, therefore, demonstrating the severity of this disease. Prospective studies evaluating other treatments are necessary to address the impact of local treatments in liver metastasis in MPC. OPEN ACCESSCitation: Usón PLS, Junior, Tolentino FD'AvilaS, Santos VM, Rother ET, Maluf FC (2020) The impact of metastatic sites in advanced pancreatic adenocarcinoma, systematic review and metaanalysis of prospective randomized studies. PLoS ONE 15(3): e0230060. https://doi.org/10.

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“…Masitinib's activity in imatinib-naïve GIST has previously been reported as sustainable and well-tolerated, and also in imatinib-resistant GIST with less toxicity reported as compared with sunitinib 10 . Masitinib indications are supposed to be much wider, as have documented very hopeful results published recently in indication of pancreatic cancer 11 . Hence, there is strong medical plausibility that masitinib will have a therapeutic benefit in advanced melanoma patients harboring a mutation in the juxtamembrane domain of KIT.…”

Section: Discussionmentioning

confidence: 98%

Rapid and clinically significant response to masitinib in the treatment of mucosal primary esophageal melanoma with somatic KIT exon 11 mutation involving brain metastases: A case report

Prošvicová¹,

Lukesová²,

Kopecký³

et al. 2015

BIOMED PAP

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Background. Malignant melanoma in the gastrointestinal tract may be primary or metastatic. Mucosal melanoma is a quite rare and aggressive disease, growing hidden and diagnosed with a certain delay which makes treatment difficult. Case Report. The authors present the first patient with c-kit exon 11 mutated primary esophageal melanoma treated with oral tyrosine kinase inhibitor masitinib. A 55-year-old-man presented with esophageal melanoma metastising into visceral organs and to the brain. The patient showed objective and clinical significant therapeutic response to masitinib. After initiation of masitinib, dysphagia and odynophagia disappeared within 1 week. Following 1 month of treatment, computed tomography showed a regression in the number and size of brain metastatic lesions and regression in visceral lesions. This therapeutic response, despite the aggressive disease on treatment initiation, effectively enabled the patient to have 6 months of quality life. Conclusion. This report corroborates the plausibility of treating advanced melanoma carrying a mutation of KIT with masitinib. It also raises the question of masitinib treatment beyond progression. Additionally, the observed masitinib treatment effect on the brain suggests accumulation of therapeutically relevant concentration of masitinib in the central nervous system. This observation has possible ramifications for treatment of intracranial neoplasms.

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A randomized, placebo-controlled phase III trial of masitinib plus gemcitabine in the treatment of advanced pancreatic cancer

Cited by 80 publications

References 11 publications

Mast Cells Density Positive to Tryptase Correlate with Microvascular Density in both Primary Gastric Cancer Tissue and Loco-Regional Lymph Node Metastases from Patients That Have Undergone Radical Surgery

Mast Cells Density Positive to Tryptase Correlate with Microvascular Density in both Primary Gastric Cancer Tissue and Loco-Regional Lymph Node Metastases from Patients That Have Undergone Radical Surgery

The impact of metastatic sites in advanced pancreatic adenocarcinoma, systematic review and meta-analysis of prospective randomized studies

Rapid and clinically significant response to masitinib in the treatment of mucosal primary esophageal melanoma with somatic KIT exon 11 mutation involving brain metastases: A case report

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