Masitinib in Oncology



Prostate Cancer

Prostate cancer is one of the most common types of cancer in men.

Masitinib is currently investigated in first-line metastatic castrate-resistant prostate cancer (mCRPC).

This patient population consists of patients who have disease progression despite androgen depletion therapy (castration) treatment.

There is still a need for more effective first-line treatment of mCRPC since recent therapies approved for CRPC are drugs used either prior to chemotherapy or used for non-metastatic castrate-resistant prostate cancer.


Evidence indicates that recruitment of inflammatory cells facilitates the growth and spread of some cancers, including prostate cancer, by producing molecules that enhance tumor invasiveness. Indeed, there is a known association between inflammation and advanced prostate cancer development [Kazma, 2012; Aldemir, 2010].

Mast cells are known to orchestrate inflammatory processes and contribute to the inflammatory cascade by merit of the wide array of pro- inflammatory mediators they release. Moreover, Taverna et al and Johansson et al have demonstrated mast cells to be independent prognositic markers for prostate cancer progression [Taverna, 2013; Johansson, 2010].

 

Summary of prostate cancer clinical program with masitinib

Phase Design Population Primary Target Patient Target IDMC recommandation Study Status Related publications
1/2 Prospective, open-label, 2 parallel-group study Patients with Hormone Refractory Prostate Cancer (HRPC) in progression after first line of treatment Overall Survival (OS) 34 NA Study completed -
3 Prospective, double-blind, placebo-controlled, 2-parallel groups study Patients with metastatic Castrate Resistant Prostate Cancer Progression Free Survival (PFS) 470 Continuation of the study without resampling option (based on interim analysis and safety data) Recruitment ongoing -



Phase 1/2 proof of concept

Clinical phase 1/2 proof of concept with masitinib in prostate cancer supported the development of masitinib in prostate cancer in combination with docetaxel. This phase 1/2 study which included patients with Hormone Refractory Prostate Cancer (HRPC) in progression after first line of treatment, tested the combination of masitinib with docetaxel. The median overall survival reached 18.4 months in the masitinib plus docetaxel arm with a lower bound of the corresponding one-sided 75% CI of 17.8 months. This median OS compared favorably to a meta-analysis of overall survival of 14.4 months (after the arrival of enzalutamide).


Phase 3 study

AB Science launched a phase 3 study to assess the safety and efficacy of masitinib in combination with docetaxel to placebo in combination with docetaxel in first line metastatic castrate resistant prostate cancer.
 
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.
 
In June 2018, a pre-planned interim analysis was performed once 50% of the events had been reached and the IDMC recommended the continuation of study in a pre-specified sub-population of patients that were identified based on a specific biological biomarker, and estimated to account for about two-thirds of the eligible population.
 
Study recruitment is ongoing.

 

Development of prostate cancer is often driven by male sex hormones called androgens, including testosterone. Castrate-resistant prostate cancer occurs when prostate cancer grows despite the use of androgen-deprivation therapy to block the action of male sex hormones. Metastatic CRPC (mCRPC) occurs when the cancer spreads to other parts of the body. Castrate-resistant prostate cancer is defined by disease progression despite androgen depletion (hormone) therapy and may present as either a continuous rise in serum prostate-specific antigen (PSA) levels, the progression of pre-existing disease, and/or the appearance of new metastases.
 
Prostate cancer is the most common cause of cancer in men. There were an estimated 1.6 million new cases diagnosed worldwide in 2015 and the American Cancer Society estimates that in the US 164,690 new cases of prostate cancer will be diagnosed in 2018. In the European Union, the estimated number of new prostate cancer cases in 2015 was 365,000.
 
Although the overall 5-year survival rate for prostate cancer is very high, up to 20% of men who undergo state-of-the art treatment for prostate cancer will develop CRPC within 5 years, and at least 84% of these will have metastases at the time of CRPC diagnosis.Likewise, almost all patients with metastatic disease become resistant to androgen-deprivation therapy.

Patients

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Pancreatic Cancer

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
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.