D3.414 - The Phase 2/3 Study of Elenestinib, a Highly Potent and Selective Tyrosine Kinase Inhibitor, in Patients With Indolent Systemic Mastocytosis

Systemic mastocytosis, including indolent systemic mastocytosis (ISM), is a clonal mast cell (MC) disease driven by D816V-mutant KIT in ~95% of cases. ISM is characterized by the accumulation and activation of aberrant MCs that may be associated with chronic and debilitating disease features, including anaphylaxis, skin lesions, gastrointestinal and neurocognitive symptoms as well as osteoporosis, which can significantly impact patients’ quality of life (QoL).

Phase 2/3 HARBOR (NCT04910685) is an ongoing study designed to evaluate the efficacy and safety of elenestinib in patients with ISM. Data from HARBOR Part 1 and pharmacokinetic (PK) groups supported 75 mg and 100 mg as tolerable and effective doses for treatment.

In HARBOR Part 2, ~354 patients will be randomized 1:1:1 to elenestinib 75 mg once daily (QD) + symptom-directed therapy (SDT), elenestinib 100 mg QD + SDT, or placebo + SDT. After completing the double-blind Part 2 (assessed at 48 weeks), patients will cross over to Part 3 to receive 75 mg or 100 mg QD elenestinib + SDT. Key inclusion criteria include centrally confirmed ISM diagnosis and 14-day average total symptom score (TSS) ≥28 evaluated by the ISM symptom assessment form (ISM-SAF; © 2018 Blueprint Medicines Corporation). The primary endpoint is the mean change in ISM-SAF TSS from baseline to 48 weeks. Key secondary endpoints include proportions of patients achieving normalisation of tryptase, undetectable or ≥50% reduction in KIT D816V variant allele fraction, and symptom control, change in bone mineral density, change in anaphylaxis frequency, and change in QoL. Secondary endpoints include disease control assessed via patient-reported Mastocytosis Control Test, change in SDT use, and change in skin lesions. Safety data will also be collected.

Trial in progess.

HARBOR Part 2 has been optimized based on Part 1 and emerging evidence to include dosing flexibility by evaluating two active doses, endpoints that evaluate disease modification beyond symptom control, including anaphylaxis control and bone health, and timing of endpoints that reflect the chronic nature of the disease. HARBOR Part 2 has initiated, and the number of total sites has been expanded internationally.