Investigational Drug BLU-285 Shows Tolerable Safety, Early Clinical Activity in Patients With Advanced Systemic Mastocytosis

Data from an ongoing phase I trial of BLU-285, an oral inhibitor of KIT D816V, in patients with advanced systemic mastocytosis (SM) suggest that the investigational agent is well tolerated and could alleviate symptom burden in this setting.

KIT D816V is a key driver of SM and is present in approximately 95 percent of SM cases; however, available therapies do not effectively target this mutation, study investigators, led by Mark Drummond, MBChB, PhD, from the Beatson West of Scotland Cancer Centre at the National Health Services Greater Glasgow and Clyde in the United Kingdom, explained. Co-investigator Daniel DeAngelo, MD, PhD, of Dana-Farber Cancer Institute in Boston, Massachusetts, presented the findings at the 2016 ASH Annual Meeting.

Adult patients with aggressive SM, SM with associated hematologic non-mast cell disorder, and mast cell leukemia were eligible for study inclusion and received BLU-285 once daily on a four-week cycle following a “3+3” dose-escalation design. The investigators assessed pharmacokinetic and biomarkers, D816V mutant allele fraction in blood and bone marrow (BM), and co-occurring mutations, as well as liver and spleen size.

As of the data cut-off point on November 11, 2016, 12 patients have been treated with BLU-285 at three dose levels (30 mg, 60 mg, or 100 mg once daily). The median age was 61.5 years (range = 39-82 years), and, as the investigators expected, most patients (n=11/12) had KIT D816V mutation. All patients had mast cell–related organ damage, defined as one of the following: bone marrow dysfunction with ≥ 1 cytopenia; hepatomegaly with impaired liver function, ascites and/or portal hypertension; osteolytic skeletal lesions; splenomegaly with hypersplenism; or malabsorption with weight loss. Patients had a median of 1.5 of these symptoms (range = 1-3).

Ten of the 12 patients remained on the clinical trial as of the data cut-off date, with treatment duration ranging from 1 month to 8.1 months. BLU-285 appeared to be well tolerated at all doses; no patients discontinued treatment due to adverse events (AEs), and no grade ≥4 AEs were reported. The majority of the AEs were grade 1 or 2 and included fatigue, dizziness, headache, rash, shingles, anemia, and thrombocytopenia (n=1 for each). Grade 3 alkaline phosphatase elevation was observed in three patients, and all three cases were asymptomatic and transient, the investigotors reported.

“These elevations occurred in the three patients with the highest bone marrow mast cell burden at baseline, suggesting this may be consistent with a pharmacodynamic effect of BLU-285 on mast cells in the bone,” they added. “One of the three cases of alkaline phosphatase elevation was considered possibly treatment-related and defined as a dose-limiting toxicity at the 60 mg dose level.” However, all three patients continued treatment with BLU-285 without a dose reduction.

A maximum-tolerated dose (MTD) has not yet been established. This phase I trial continues to enroll patients, with a target enrollment of 60 patients, including 25 in the dose-escalation phase and 35 in the dose-expansion phase.

Objective decreases in mast cell burden were also observed in six of eight evaluable patients, including decline in peripheral blood and BM KIT D816V DNA levels (n=6) – five of whom experienced this reduction within the first two treatment cycles. Serum tryptase levels declined in 10 of 12 patients, eight of whom had a decrease greater than 50 percent. BM biopsy also revealed that six patients experienced a decrease in BM mast cell infiltrate – three of whom had a decrease greater than 50 percent from baseline, and one of whom had no residual BM mast cells.

Although these are preliminary data, the investigators reported “marked improvements in disease symptoms and burden” across all patients in all dose levels – a secondary objective of the study. These included symptomatic relief of allergy symptoms and a decreased use of corticosteroids to manage these symptoms, improved urticaria pigmentosa (an allergy-mediated rash common in SM patients), and increased albumin/weight gain (indicating improvements in malabsorption).

“Advanced systemic mastocytosis is a rare and severe disease that shortens life expectancy with a wide range of debilitating symptoms and organ damage,” Dr. DeAngelo said, noting the need for treatments that address the underlying cause of this disease. “The objective decreases in mast cell burden and improvements in symptoms seen in these early data are encouraging.”


Drummond M, DeAngelo DJ, Deininger MW, et al. Preliminary safety and clinical activity in a phase 1 study of blu-285, a potent, highly-selective inhibitor of KIT D816V in advanced systemic mastocytosis (SM). Abstract #477. Presented at the 2016 ASH Annual Meeting, December 4, 2016; San Diego, California.