Novel Agent Shows Promise in Phase 2 Trial of Mastocytosis

The novel agent midostaurin (PKC412) showed promise for the treatment of patients with advanced systemic mastocytosis in a phase 2 study, as it elicited an overall response rate of 60 percent. Results were published in late June in The New England Journal of Medicine.

Mastocytosis is a rare disorder — systemic mastocytosis affects about 8,000 individuals in the U.S. — caused by an abnormal buildup of mast cells (a type of immune cells) in bone marrow, skin and other organs of the body. Patients with advanced systemic mastocytosis typically live less than six months to three and a half years, and there are no approved treatments for the majority of patients.

“Patients with advanced [systemic mastocytosis] are part of a very small, highly underserved community that has suffered from a lack of medical innovation for many years,” Alessandro Riva from Novartis, said in a statement. “Novartis is proud to have developed a treatment that shows benefit for these patients, and is now working with regulatory authorities to make midostaurin available as quickly as possible.”

This phase 2 study was the largest and longest-running prospective clinical trial ever in this disease, according to a press release from Novartis, the company developing the drug. Midostaurin is an oral multi-targeted kinase inhibitor that has a Breakthrough Therapy Designation status for a subset of adults with acute myeloid leukemia (AML) and orphan drug status for AML and mastocytosis. Both statuses allow for quicker development and increased communication between the pharmaceutical company and the FDA.

In total, 116 patients received 100 mg of oral midostaurin twice per day, though 89 were included in the primary efficacy population due to mastocytosis-related organ data. The 89 individuals were classified by disease subtype: 16 had aggressive systemic mastocytosis (18 percent), 57 had systemic mastocytosis with an associated hematologic neoplasm (64 percent) and 16 had mast-cell leukemia (18 percent). Patients were also classified according to KIT D816 mutation status: 77 were positive (87 percent), 10 were negative (11 percent) and 2 had unknown status (2 percent).

In total, 53 patients experienced a major or partial response, equating to a 60 percent overall response rate. Overall response rates were similar between subtypes: 12 of 16 patients with aggressive systemic mastocytosis (75 percent), 33 of 57 patients with systemic mastocytosis with an associated hematologic neoplasm (58 percent) and 8 of 16 patients with mast-cell leukemia (50 percent). The overall duration of response among all patients on the trial was 24.1 months. Response rates were also similar, the authors noted, regardless KIT D816V mutation status and previous treatment.

“These data show clear disease and symptom improvement with oral midostaurin treatment across a range of study participants who were reflective of the heterogeneity of this disease,” Andreas Reiter, a professor from the University of Heidelberg in Germany and senior author of the study, said in a statement. “If approved, midostaurin will offer patients a much needed treatment option.”

The most common side effects on the trial (among the total population of 116) were nausea, vomiting, diarrhea and peripheral edema. Nausea occurred in 92 patients (79 percent), vomiting in 77 patients (66 percent), diarrhea in 63 patients (54 percent) and peripheral edema in 40 patients (34 percent).

Grade 3 or 4 events associated with treatment were observed in far fewer patients: 7 patients (6 percent) experienced grade 3 or 4 nausea, 7 patients (6 percent) experienced grade 3 or 4 vomiting, 9 patients (8 percent) experienced grade 3 or 4 diarrhea and 5 patients (4 percent) experienced grade 3 or 4 peripheral edema.

This study gave researchers “initial evidence” for the efficacy of midostaurin to benefit patients with regard to reversing organ damage, decrease splenomegaly (enlargement of the spleen), improve quality of life and more, the study’s authors noted.

“Future studies are warranted to evaluate midostaurin in combination with other drugs and in the peritransplantation setting in patients with advanced systemic mastocytosis, or as monotherapy in patients with indolent systemic mastocytosis with refractory symptoms,” the authors wrote.