Overview
This is a randomized, double-blind, placebo-controlled, Phase 2/3 study comparing the efficacy and safety of BLU-263 + best supportive care (BSC) with placebo + BSC in patients with indolent systemic mastocytosis (ISM) whose symptoms are not adequately controlled by BSC. Parts 1 and 2 will enroll patients with ISM. Patients enrolled in Part 1 or Part 2 will roll over onto Part 3 to receive treatment with BLU-263 in an open-label fashion following completion of the earlier Part. Part M will enroll patients with monoclonal mast cell activation syndrome (mMCAS). The study also includes PK groups that will enroll patients with ISM.
Eligibility
Key Inclusion Criteria:
All Patients
-1. Patient must have an Eastern Cooperative Oncology Group Performance Status (ECOG PS) of
0 to 2.
Part 1 and Part 2
- 2. Patient must have moderate-to-severe symptoms based on minimum mean total symptom
score (TSS) of the ISM Symptom Assessment Form (ISM-SAF) over the 14-day eligibility
screening period.
- 3. Patient has confirmed diagnosis of ISM, confirmed by Central Pathology Review of BM
biopsy and central review of B- and C-findings by WHO diagnostic criteria. Archival
biopsy may be used if completed within the past 12 months.
- 4. Patient must have failed to achieve adequate symptom control for 1 or more Baseline
symptoms, as determined by the Investigator, with at least 2 of the following
symptomatic therapies administered: H1 blockers, H2 blockers, proton-pump inhibitors,
leukotriene inhibitors, cromolyn sodium, corticosteroids, or omalizumab.
- 5. Patients must have BSC for ISM symptom management stabilized for at least 14 days
prior to starting screening procedures.
- 6. For patients receiving corticosteroids, the dose must be ≤ 20 mg/d prednisone or
equivalent, and the dose must be stable for ≥ 14 days.
Part M
- 7. Patients must have mMCAS, confirmed by Central Pathology Review of BM biopsy. An
archival biopsy may be used if completed within the past 12 months.
- 8. Patients must have tryptase < 20 ng/mL.
- 9. Patients must have KIT D816V in peripheral blood (PB) or BM and/or CD25+ Mast cells
in BM.
- 10. Patients must have symptoms consistent with mast cell activation (despite BSC) in
at least two organ systems characterized by cutaneous flushing, tachycardia, syncope,
hypotension, diarrhea, nausea, vomiting and gastro-intestinal cramping) and serum
blood tryptase (sBT) levels above 8 ng/mL OR Severe (Ring and Messmer grading ≥ II,
recurrent anaphylaxis, including but not limited to hymenoptera venom, drug or food,
regardless of sBT levels.
PK Groups
- 11. See inclusion criteria for All patients and Part 1/Part 2
- 12. Accrual may be limited to patients who have specific disease manifestations (ie,
GI involvement) or are taking acid-reducing agents to better explore the impact of
these features on PK.
Key Exclusion Criteria:
- 1. Patient has been diagnosed with any of the following WHO systemic mastocytosis (SM)
sub-classifications: cutaneous mastocytosis only, smoldering SM, SM with associated
hematologic neoplasm, aggressive SM, mast cell leukemia, or mast cell sarcoma.
- 2. Patient has been diagnosed with another myeloproliferative disorder.
- 3. Patient has organ damage C-findings attributable to SM.
- 4. Patient has clinically significant, uncontrolled, cardiovascular disease
- 5. Patient has a QT interval corrected using Fridericia's formula (QTcF) > 480 msec.
- 6. Patient has previously received treatment with any targeted KIT inhibitors.
- 7. Patient has a history of a primary malignancy that has been diagnosed or required
therapy within 3 years. The following prior malignancies are not exclusionary:
completely resected basal cell and squamous cell skin cancer, curatively treated
localized prostate cancer, and completely resected carcinoma in situ of any site.
- 8. Time since any cytoreductive therapy including mastinib and midostaurin should be
at least 5 half-lives or 14 days (whichever is longer), and for cladribine, interferon
alpha, pegylated interferon, or antibody therapy < 28 days or 5 half-lives of the drug
(whichever is longer), before beginning the screening period.
- 9.Patient has received radiotherapy or psoralen and ultraviolet A (PUVA) therapy < 14
days before beginning the screening period.