Ensayos clínicos

Inclusion Criteria:

Entry Criteria for All Patients:

• Patients are eligible to be included in the study only if all of the following criteria apply:
  • Patient must be ≥ 16 years of age at the time of signing the informed consent/assent. (In France, Sweden, Germany, and Spain, only patients who are ≥ 18 years of age are allowed);
  • Patient or legally authorized representative provides signed informed consent/assent to participate in the study, based on local regulations. If a patient is < 18 years of age, a parent or guardian provides signed informed consent as required;
  • Patient must have an Eastern Cooperative Oncology Group Performance Status (ECOG PS) of 0 to 2.

Entry Criteria for Patients with ISM in Part 1 and Part 2:

• In Part 1, patient must have a minimum 14-day average TSS of ≥ 28 during the eligibility period. In Part 2, patients with minimum 14-day average TSS ≥ 28 and TSS < 28 with a minimum of 20 during the eligibility period can be enrolled. If applicable, 14-day average TSS for eligibility and Baseline should not be calculated until all COVID-19 vaccine and/or COVID-19 infection- related symptoms have returned to baseline/resolved.

Entry Criteria for Patients with ISM in Part 1, Part 2 and PK Groups:

• 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.
• Patient must have failed to achieve adequate symptom control for 1 or more Baseline symptoms as determined by the Investigator’s best clinical judgement, with at least 2 of the following symptomatic therapies administered: H1 blockers, H2 blockers, protonpump inhibitors, leukotriene inhibitors, cromolyn sodium, corticosteroids, or omalizumab.
• Patients must have BSC for ISM symptom management stabilized without any new or worsening of symptoms and or AE’s for at least 14 days prior to starting 14-day ISMSAF TSS eligibility period.
• The patient’s ISM symptomatic therapies (e.g., H1 and H2 blockers) must be stable (same dose, no new medications ≥ 14 days before beginning the 14-day eligibility Screening Period for the assessment of ISM-SAF).
• If the patient is receiving corticosteroids, the dose must be ≤ 20 mg/day prednisone or equivalent, and the dose must be stable for ≥ 14 days before beginning the 14-day eligibility Screening Period for assessment of ISM-SAF (see Section 4.1.1 for more information on use of corticosteroid use during patient screening).

Entry Criteria for Patients with mMCAS in Part M:

• Criteria specific to inclusion in Part M in addition to Entry Criteria for all patients are: 10. 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.
• Patients must have tryptase < 20 ng/mL.
• Patients must have KIT D816V in peripheral blood (PB) or BM and CD25 + Mast cells in BM.
• Patients must have symptoms consistent with mast cell activation (despite BSC) in at least 2 organ system 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, [Section 14.15]), recurrent anaphylaxis, including but not limited to hymenoptera venom, drug or food, regardless of sBT levels. Entry Criteria for Patients with ISM in PK Groups:
• For PK Group enrolled prior to or in parallel to Part 1, patients with a 14-day average TSS score of < 28 and a single domain score of at least 7 may be enrolled. For PK Group prior to Part 2, patients with 14-day average TSS of ≥ 20 during the eligibility period may be enrolled.
• Accrual may be limited to patients who have specific disease manifestations (i.e., GI involvement) to better explore the impact of these features on PK.

Exclusion Criteria:

Patients are excluded from the study (all parts) if any of the following criteria apply:

• Patient has been diagnosed with any of the following WHO SM subclassifications:
  • Cutaneous mastocytosis only (i.e., without documentation of systemic involvement);
  • Smoldering systemic mastocystosis (SSM);
  • Systemic mastocytosis with an associated hematologic neoplasm of non-MC lineage (SM-AHN);
  • Aggressive systemic mastocytosis (ASM);
  • Mast cell leukemia (MCL);
  • MC sarcoma.
• Patient has been diagnosed with another myeloproliferative disorder (e.g., myelodysplastic syndrome, myeloproliferative neoplasm).
• Patient has any of the following organ damage C-findings attributable to SM:
  • Cytopenia:
  • Absolute neutrophil count < 1.5 × 109 /L.;
  • Hemoglobin < 10 g/dL;
  • Platelet count < 100,000/µL;
  • Hepatomegaly with ascites and/or portal hypertension with or without impaired liver function;
  • Palpable splenomegaly with hypersplenism;
  • Malabsorption with hypoalbuminemia and significant weight loss;
  • Skeletal lesions: large osteolytic lesions with pathologic fractures;
  • Life-threatening organ damage in other organ systems that is caused by MC infiltration in tissues.
• Patient meets any of the following laboratory criteria:
  • Aspartate aminotransferase or alanine aminotransferase > 3.0 × upper limit of normal (ULN);
  • Total bilirubin > 1.5 × ULN; > 3.0 × ULN if due to Gilbert's disease;
  • Albumin < 1 × lower limit of normal (LLN);
  • Estimated glomerular filtration rate (eGFR; calculated using the Modification of Diet in Renal Disease equation) < 30 mL/min/1.73 m2 or creatinine > 1.5 × ULN
• Patient has a QT interval corrected using Fridericia's formula (QTcF) > 470 msec (for females) or > 450 msec (for males).
• Patient has clinically significant, uncontrolled, cardiovascular disease including congestive heart failure Grade III or IV according to the New York Heart Association classification; myocardial infarction or unstable angina within the previous 6 months, uncontrolled hypertension, or clinically significant, uncontrolled arrhythmias, including bradyarrhythmias that may cause QT prolongation (e.g., Type II second degree heart block or third-degree heart block).
• Patient has previously received treatment with any selective KIT inhibitors (avapritinib, bezuclastinib, and ripretinib).
• Patients requiring anticoagulant therapy such as warfarin, or similar agents requiring therapeutic international normalized ratio (INR) monitoring.
• Patient has had a major surgical procedure within 14 days before beginning the Screening assessments.
• 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.
• Time since any cytoreductive therapy including masitinib 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 assessments. For omalizumab, washout is not necessary and patients can continue on omalizumab therapy.
• Patient has received radiotherapy or psoralen and ultraviolet A (PUVA) therapy < 14 days before beginning the Screening assessments.
• Patient has received any hematopoietic growth factor during the preceding 14 days before beginning the Screening assessments.
• Patient requires therapy with a concomitant medication that is a strong inhibitor, strong inducer, or moderate inducer of cytochrome P450 3A4 (CYP3A4).
• Patient has a history of a seizure disorder (e.g., epilepsy) or requires antiseizure medication. Patient has a history of a cerebrovascular accident or transient ischemic attacks within 12 months before the first dose of study drug.
• Patient has a known risk or recent history (12 months before the first dose of study drug) of intracranial bleeding (eg, brain aneurysm).
• Patient is receiving an investigational agent in another interventional study.
• Women who are unwilling, if not post-menopausal or surgically sterile, to abstain from sexual intercourse or employ highly effective contraception and a barrier method from the time of informed consent and for at least 30 days after the last dose of study treatment. Men who are unwilling, if not surgically sterile, to abstain from sexual intercourse or employ highly effective contraception and a barrier method from the time of informed consent and for at least 90 days after the last dose of study treatment. 
• Patient is pregnant, as documented by a serum beta human chorionic gonadotropin (β-hCG) pregnancy test consistent with pregnancy obtained within 7 days before the first dose of study treatment. Patients with β-hCG values that are within the range for pregnancy but are not pregnant (false-positives) may be enrolled with written consent of the Sponsor after pregnancy has been ruled out. Women of non-childbearing potential (post-menopausal for more than 1-year, bilateral tubal ligation, bilateral oophorectomy, or hysterectomy) do not require a serum β-hCG test.
• Patient is breastfeeding.
• Patient has prior or ongoing clinically significant illness, medical condition, surgical history, physical finding, or laboratory abnormality that, in the Investigator's opinion, could affect the safety of the patient; alter the absorption, distribution, metabolism, or excretion of the study drug; or impair the assessment of study results. Patients with uncontrolled symptomatic illnesses unrelated to mastocytosis that may impact the ISMSAF or QoL assessments (e.g., Crohn’s Disease, ulcerative colitis, psoriasis, or sickle cell anemia) are excluded from the study.
• Patient is unwilling or unable to comply with scheduled visits, treatment administration plan, laboratory tests, or other study procedures and study restrictions.
• Patient has known hypersensitivity to BLU-263 or to any of the excipients.
• Employees, contracted agents, or their dependents of the sponsor, Investigator, or clinical trial site.
• Patient is institutionalized based on an administrative or court order (Germany Only).
• Patients who have previously experienced reactions to local anesthesia will be excluded from the study.

Note: Other protocol defined Inclusion/Exclusion Criteria may apply.

Eligibility last updated 9/7/23. Questions regarding updates should be directed to the study team contact.