Blu-285 demonstrates activity in advanced systemic mastocytosis

SAN DIEGO — The investigational agent BLU-285 appeared active and safe in patients with advanced systemic mastocytosis, according to study results presented at the ASH Annual Meeting and Exposition.

In dose-escalation studies, BLU-285 (Blueprint Medicines) — a highly selective inhibitor of KIT D816V — conferred decreases in disease burden and disease-related organ damage.

“These encouraging ... data support selective targeting of KIT D816V and further clinical testing of BLU-285 in systemic mastocytosis,” Mark Drummond, MBChB, PhD, FRCPath, consultant hematologist and honorary senior lecturer at The Beatson West of Scotland Cancer Centre in Glasgow, and colleagues wrote.

Aggressive systemic mastocytosis is a mast cell neoplasm that causes debilitating allergy symptoms, dramatically impairs organ function and shortens life expectancy, according to study background.

KIT D816V mutations are a key genomic driver in nearly 95% of patients with systemic mastocytosis. However, no approved therapies target this mutation.

Drummond and colleagues assessed the safety, pharmacokinetics and preliminary activity of BLU-285 in adults with advanced systemic mastocytosis or related disorders, including systemic mastocytosis with associated hematologic nonmast cell disorder or mast cell leukemia.

Study participants received BLU-285 once daily on a 4-week cycle following a 3+3 escalation design.

Investigators assessed adverse events, pharmacokinetics and biomarkers, including D816V mutant allele fraction in blood and bone marrow, co-occurring mutations and serum tryptase. They also measured liver and spleen size via CT or MRI.

At data cutoff, six patients had been treated in two cohorts at doses of 30 mg/day or 60 mg/day.

All participants had confirmed D816V mutations in their blood and bone marrow. They all had at least one (range, 4-9) co-occurring mutation in the bone marrow, the most common of which were TET2 (n = 5), DNMT3A (n = 4) and GATA1 (n = 4).

All patients experienced disease-related organ damage as determined by at least one C-finding (median, 1.5; range, 1-3), such as hepatomegaly with impaired liver function, ascites or portal hypertension; bone marrow dysfunction with at least one cytopenia; osteolytic skeletal lesions; malabsorption with weight loss; or splenomegaly with hypersplenism. Four patients had urticaria pigmentosa.

Five patients received concomitant antihistamines for disease-related symptoms. Two each received concomitant corticosteroids or leukotriene receptor antagonists, and one received cromolyn. Two had received prior antineoplastic therapy (pegylated interferon, n = 1; midostaurin, n = 1).

Results showed “marked improvements in disease symptoms and burden” among all patients, regardless of dose, Drummond and colleagues wrote. Two patients achieved symptomatic relief of allergy symptoms with decreased use of corticosteroids; three of four patients with urticaria pigmentosa experienced improvement; five patients demonstrated increased albumin and all six gained weight.

All six patients achieved objective decreases in mast cell burden as evidenced by decline in KIT D816V DNA levels in peripheral blood and bone marrow (n = 6), tryptase decline (n = 5), decreased splenomegaly (n = 3). Both patients with mast cells in bone marrow experienced declines. One patient’s level declined from 30% at baseline to 3% by the start of the third treatment cycle; another had bone marrow biopsy mast cell decline from 80% to 20% by the start of the third treatment cycle.

Results suggest tryptase decline is associated with dose. All three patients assigned the 60-mg dose achieved greater than 50% tryptase decline, whereas one of three patients assigned the 30-mg dose achieved the same decline.

BLU-285 appeared well tolerated. Most adverse events were grade 1. Grade 2 adverse events included one case each of fatigue, dizziness, rash, headache, shingles, anemia, elevated gamma-glutamyl transferase and thrombocytopenia. Three patients experienced grade 3 alkaline phosphatase elevation and one experienced grade 3 back pain. No grade 4 or higher events occurred.

All patients remained on treatment at the time of analysis, with treatment durations ranging from two to five cycles.

“Currently approved therapies do not effectively target KIT D816V, a key genomic-driver in ... systemic mastocytosis,” Drummond and colleagues wrote. “BLU-285 — a potent, highly selective inhibitor of this mutant — has been well tolerated and demonstrates clinical activity early in dose escalation with objective decreases in mast cell burden and improvements in mast cell–related organ damage in advanced systemic mastocytosis.” – by Mark Leiser

Reference: Drummond M, et al. Abstract 477. Presented at: ASH Annual Meeting and Exposition; Dec. 3-6, 2016; San Diego.

Disclosure: Drummond reports consultant and speakers bureau roles with, honoraria and research funding from, or travel, accommodations or other expenses from Bristol-Myers Squibb, Celgene, CTI BioPharma, Gilead, Novartis and Roche. Please see the abstract for a list of all other researchers’ relevant financial disclosures.