Masitinib in Oncology

Pancreatic cancer is almost always fatal. Patients diagnosed with pancreatic cancer often have a poorer prognosis compared with other cancers in part because early detection is difficult.

Masitinib is currently investigated in non-resectable locally advanced or metastatic pancreatic cancer, restricted to patients with cancer related pain.

In recognition of the critical need for new treatments, masitinib received orphan drug designation for pancreatic cancer from both the European Medicine Agency (EMA) and the U.S. Food and Drug Administration (FDA).

The potential therapeutic benefit of masitinib in combination with gemcitabine for the treatment of advanced pancreatic ductal adenocarcinoma (PDAC) has been previously reported in preclinical studies, wherein masitinib was shown to enhance the antiproliferative activity of gemcitabine in gemcitabine–refractory pancreatic cancer cell lines [Humbert, 2010].

There is a growing body of evidence suggesting that heterogeneity in tumor biology and microenvironment may be an important determinant of survival difference amongst groups of PDAC patients (i.e. aggressive versus relatively slow disease progression, as seen in routine clinical practice), which in turn leads to variability in terms of treatment susceptibility and potential failure of targeted drugs in the overall population. It has been reported that such heterogeneity in PDAC patients may be associated with increased mast cell infiltration into the tumor or tumor microenvironment, both of which are prognostic factors for poor survival in PDAC [Protti, 2013; Chang, 2011]. Masitinib is a highly selective inhibitor of mast cell function and activity.

Summary of pancreatic cancer clinical program with masitinib

Phase	Design	Population	Primary Target	Patient Target	IDMC recommandation	Study Status	Related publications
2a	Open-label, single group study	Patients with advanced pancreatic cancer	Time to Tumor Progression (TTP)	22	NA	Study completed	Mitry, 2010
2/3	Prospective, double-blind, placebo-controlled, 2-parallel groups study	Patients with advanced/metastatic pancreatic cancer	Overall survival (OS)	350	NA	Study completed	Delplanque, 2015
3	Prospective, double-blind, placebo-controlled, 2-parallel groups study	Patients with non resectable locally advanced or metastatic pancreatic cancer	Overall survival (OS)	380	Continuation of the study (based on safety data)	Recruitment ongoing	–

Phase 2a proof of concept

Clinical phase 2a proof of concept with masitinib in pancreatic cancer supported the development of masitinib in pancreatic cancer. In this study, patients with unresectable, locally advanced or metastatic pancreatic cancer received oral masitinib combined with standard gemcitabine. The primary endpoint of median Time To Progression (TTP) was 6.4 months (95% CI [2.7–11.7]). Median Overall Survival (OS) was 7.1 months (95% CI [4.8–17.0]).

Phase 2/3 studies

First phase 2/3 study

AB Science completed a phase 3 study to compare efficacy and safety of masitinib in combination with gemcitabine, to placebo in combination with gemcitabine, in treatment of patients with advanced/metastatic pancreatic cancer.

Despite, the median Overall Survival (OS) for the overall population was similar for both treatment-arms, ex-post analysis showed that masitinib in combination with gemcitabine extended the OS in the patients with cancer pain sub-population, representing 45% of the overall population.

In this pain subgroup, patients treated with masitinib plus gemcitabine had a median OS of 8.0 months [95% CI (5.8; 11.5)] compared with a median OS of 5.4 months [95% CI (3.7; 8.3)] for the placebo plus gemcitabine treatment-arm, an OS gain of + 2.6 months. The corresponding HR was 0.62 [95% CI (0.43; 0.89), P = 0.012].

These findings seem consistent with the mechanism of action of masitinib which inhibits the activity of mast cell. Current hypothesis is that pain flags the presence of mast cells in the tumor microenvironment and mast cell activation may help transform the tumors into a more aggressive form.

Second phase 3 study

AB Science launched a confirmatory study to compare efficacy and safety of masitinib in combination with gemcitabine to gemcitabine in combination with placebo in patients with non resectable locally advanced or metastatic pancreatic cancer, restricted to patients with cancer pain; this indication corresponding to the subgroup of efficacy from the first phase 3 study.

The Independent Data Safety and Monitoring Committee (IDMC) has, on each occasion, recommended the continuation of this phase 3 study based on the analysis of the safety data.

Study recruitment is ongoing.

Incidence of pancreatic cancer has markedly increased over the last few decades. Pancreatic cancer is now the twelfth most common cancer in the world. This cancer is almost always fatal, and is the seventh most common cause of death from cancer. Patients diagnosed with pancreatic cancer often have a poorer prognosis compared with other cancers in part because early detection is difficult. At the time of diagnosis, most patients with pancreatic adenocarcinoma present with locally advanced or metastatic disease and only 10-20% of cases are candidates for curative surgery.

A randomized, placebo-controlled phase III trial of masitinib plus gemcitabine in the treatment of advanced pancreatic cancer.
Deplanque G, Demarchi M, Hebbar M, Flynn P, Melichar B, Atkins J, Nowara E, Moyé L, Piquemal D, Ritter D, Dubreuil P, Mansfield CD, Acin Y, Moussy A, Hermine O, Hammel P.
Ann Oncol. 2015 Jun;26(6):1194-200. doi: 10.1093/annonc/mdv133. Epub 2015 Apr 9.

Safety and activity of masitinib in combination with gemcitabine in patients with advanced pancreatic cancer.
Mitry E, Hammel P, Deplanque G, Mornex F, Levy P, Seitz JF, Moussy A, Kinet JP, Hermine O, Rougier P, Raymond E.
Cancer Chemother Pharmacol. 2010 Jul;66(2):395-403. doi: 10.1007/s00280-010-1299-8.

Masitinib combined with standard gemcitabine chemotherapy: in vitro and in vivo studies in human pancreatic tumour cell lines and ectopic mouse model.
Humbert M, Castéran N, Letard S, Hanssens K, Iovanna J, Finetti P, Bertucci F, Bader T, Mansfield CD, Moussy A, Hermine O, Dubreuil P.
PLoS One. 2010 Mar 4;5(3):e9430. doi: 10.1371/journal.pone.0009430.

Masitinib in treatment of pancreatic cancer.
Waheed A, Purvey S, Saif MW.
Expert Opin Pharmacother. 2018 May;19(7):759-764. doi: 10.1080/14656566.2018.1459566. Epub 2018 Apr 11.

Dual protein kinase and nucleoside kinase modulators for rationally designed polypharmacology.
Hammam K, Saez-Ayala M, Rebuffet E, Gros L, Lopez S, Hajem B, Humbert M, Baudelet E, Audebert S, Betzi S, Lugari A, Combes S, Letard S, Casteran N, Mansfield C, Moussy A, De Sepulveda P, Morelli X, Dubreuil P.
Nat Commun. 2017 Nov 10;8(1):1420. doi: 10.1038/s41467-017-01582-5.

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Masitinib in Oncology

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