World News: 18:59 GMT Wednesday 12th June 2019. [AB Science via Globe Newswire via SPi World News]
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Study AB12005 is an international, randomized, placebo-controlled, phase 3 confirmatory study of masitinib in first-line treatment of unresectable locally advanced or metastatic pancreatic cancer patients with pain at baseline or taking opioids.
The study compares the efficacy and safety of masitinib in combination with gemcitabine to placebo in combination with gemcitabine.
The study’s primary endpoint is overall survival (OS).
The number of patients planned for enrolment was 330 patients, with patient recruitment having now been completed.
The efficacy assessment is planned in the overall study population and in the pre-specified subgroup of patients with unresectable locally advanced tumors with pain.
The distinction between unresectable locally advanced or metastatic disease status was a stratification factor, thereby ensuring that treatment-arms are unbiased for this known prognostic factor.
An interim analysis performed by the Independent Data Monitoring Committee (IDMC) was pre-planned once 50% of the events (in this case, patient death) had been reached.
The interim analysis tests futility and conditional power ≥80% (i.e. probability of success). The protocol prospectively defines the following scenarios based on findings of the interim analysis: a) stop the study if futile; b) continue the study because test with conditional power ≥ 80% is met, with or without resampling; c) in between the two abovementioned scenarios. It is scenario (b) that would make interim analysis decisive for study continuation.
In the pre specified subgroup of patients with unresectable locally advanced tumors, the IDMC recommended continuation without resampling, corresponding to scenario (b). In the overall population, interim data corresponds to scenario (a) or (c). The IDMC considered that it was not necessary to distinguish between those two scenarios because patient enrolment was complete at the time of the interim analysis. The IDMC did not recommend to discontinue any patient.
Based on the rules set for the interim analysis, the interpretation is that the probability of success of study AB12005 is above 80% in the selected sub-population, assuming that the remaining surviving patients follow a similar pattern to those analyzed at the interim analysis.
AB Science expects to report the final results from study AB12005 in 2020.
A first phase 2/3 study enabled the identification of a subgroup based on the level of pain at baseline where survival was statistically increased (+2.6 months, p=0.012, Hazard Ratio=0.62[0.43;0.89]). Pain intensity was assessed via a visual analog scale (VAS) at baseline. This linear scale provides a visual representation of pain as perceived by the patient. Pain intensity was represented by a 100 mm long, continuous line free of any internal reference marks. One extremity indicated an absence of pain (0-value) and the other extremity indicated very severe pain (100-value). The VAS threshold for the ‘pain’ subgroup was set to VAS ≥20 mm, which is consistent with established precedent from the scientific literature [1-5].
If study AB12005 shows a survival benefit, either in the subgroup of locally advanced pancreatic cancer or in the overall study population, it will corroborate this previous finding and therefore, can be considered as a confirmatory study.
There is evidence from the scientific literature in support of biological plausibility for the observed masitinib treatment-effect in patients with baseline pain (VAS ≥ 20). The presence of pain in pancreatic cancer is thought to flag an increased mast cell activity within the tumor microenvironment, which promotes disease progression. Masitinib’s highly selective inhibition of mast cell activation is expected to be of therapeutic benefit by modulating mast cell related remodeling of the tumor microenvironment.
The estimated prevalence of people living with pancreatic cancer is 21 per 100,000 . At the time of diagnosis, most patients with pancreatic ductal adenocarcinoma present with locally advanced or metastatic disease and only 10-20% of cases are candidates for curative surgery. Median overall survival is between 6 to 7 months and 1-year survival rates range between 17 to 25% [7;8]. As such, population with non-resectable pancreatic cancer in first line is around 100,000 in the EU and 60,000 in the USA.
Almost all patients experience pain in pancreatic cancer in the course of their disease. From the first study, around 50% of patients with pancreatic cancer had pain intensity (VAS > 20) or take opioids at baseline.
At least 50% of pancreatic cancer patients are patients with unresectable locally advanced tumors .
 Deplanque 2015, Ann Oncol. doi: 10.1093/annonc/mdv133.  Khazaie K, Blatner NR, Khan MW, et al. The significant role of mast cells in cancer. Cancer Metastasis Rev. Mar 2011;30(1):45-60. Theoharides TC. Mast cells and pancreatic cancer. N Engl J Med. Apr 24 2008;358(17):1860-1861. Maltby S, Khazaie K, McNagny KM. Mast cells in tumor growth: angiogenesis, tissue remodelling and immune-modulation. Biochim Biophys Acta. Aug 2009;1796(1):19-26. Christy AL, Brown MA. The multitasking mast cell: positive and negative roles in the progression of autoimmunity. J Immunol. Sep 1 2007;179(5):2673-2679
 National Cancer Institute, Pancreatic Cancer statistics, 2015Heinemann V, et al. BMC Cancer. 2008;8:82.Von Hoff DD, et al. N Engl J Med. Oct 31 2013;369(18):1691-1703. Balaban EP, et al. Locally Advanced Unresectable Pancreatic Cancer: American Society of Clinical Oncology Clinical Practice Guideline Summary. J Oncol Pract. 2017 Apr;13(4):265-269. doi: 10.1200/JOP.2016.017376.
Further information is available on AB Science’s website: .
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Globe Newswire: 18:59 GMT Wednesday 12th June 2019
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