Indolent Systemic Mastocytosis (ISM) MedDRA version: 21.1 Level: PT Classification code 10042949 Term: Systemic mastocytosis System Organ Class: 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) MedDRA version: 20.1 Level: LLT Classification code 10056452 Term: Indolent systemic mastocytosis System Organ Class: 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Conditions
Sponsors
Blueprint Medicines Corporation
Eligibility
Sex/Gender
All
Inclusion criteria
Inclusion criteria: 1. Patients who are = 18 years of age. 2. Patient must have SM, confirmed by Central Pathology Review of BM biopsy, and central review of B- and C-findings by WHO diagnostic criteria. 3. Patient must have moderate-to-severe symptoms based on minimum mean TSS over the 14-day eligibility screening period for assessment of TSS. Minimum TSS for eligibility is = 28. 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: H1 blockers, H2 blockers, proton-pump inhibitors, leukotriene inhibitors, cromolyn sodium, corticosteroids, or omalizumab. 5. The patient’s symptomatic SM therapies (eg, H1 and H2 blockers) must be stable (same dose, no new medications =14 days before beginning the 14-day ISM-SAF eligibility TSS assessment). 6. 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 ISM-SAF eligibility TSS assessment. 7. Patient must have an Eastern Cooperative Oncology Group Performance Status of 0 to 2. 8. Patient must be able to give written informed consent. Are the trial subjects under 18? no Number of subjects for this age range: F.1.2 Adults (18-64 years) yes F.1.2.1 Number of subjects for this age range 200 F.1.3 Elderly (>=65 years) yes F.1.3.1 Number of subjects for this age range 44
Exclusion criteria
Exclusion criteria: 1. Patient has been diagnosed with any of the following WHO SM subclassifications: Cutaneous mastocytosis only, SM-AHN, SSM, ASM, MCL, MC sarcoma. 2. Patient has been diagnosed with another myeloproliferative disorder. 3. Patient has any of the following organ damage C-findings attributable to SM: Cytopenia, Hepatomegaly with ascites and 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. 4. Patient meets any of the following laboratory criteria: Aspartate aminotransferase or alanine aminotransferase > 3.0 × ULN, Total bilirubin > 1.5 × ULN; > 3.0 × ULN if due to Gilbert's disease. (In the case of Gilbert’s disease, a direct bilirubin > 2.0 × ULN is an exclusion.) Albumin 1.5 × ULN Absolute neutrophil count 480 msec. 9. Patient has a history of a seizure disorder (eg, epilepsy) or requires antiseizure medication. 10. Patient has a history of a cerebrovascular accident or transient ischemic attacks within 12 months before the first dose of study drug. 11. Patient has a known risk or recent history (12 months before the first dose of study drug) of ICB (eg, brain aneurysm). 12. Patient has a primary brain malignancy or metastases to the brain. 13. Patient has clinically significant, uncontrolled cardiovascular disease, including Grade III or IV congestive heart failure greater than New York Heart Association classification II; myocardial infarction or unstable angina within the previous 6 months; clinically significant, uncontrolled arrhythmias, or uncontrolled hypertension. 14. Female patients who are unwilling, if not postmenopausal or surgically sterile, to abstain from sexual intercourse or employ highly effective contraception during the stu
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Main Objective: Part 1 - to determine the RP2D of avapritinib in patients with ISM for use in Part 2 and Part 3 of the study. Part 2 - to determine the proportion of avapritinib-treated patients with ISM achieving a =30% reduction in TSS from Baseline to C7D1, compared to placebo. Part 3 - to assess the long-term safety and efficacy of avapritinib in ISM patients.;Secondary Objective: Key Secondary (Part 2 Only) To determine from Baseline to C7D1, compared to placebo: - proportion of avapritinib-treated patients with a =50% reduction in serum tryptase - proportion of patients with a =50% reduction in peripheral blood KIT D816V allele fraction or undetectable (<0.02%) for patients with detectable mutation at Baseline - mean change in ISM-SAF TSS in patients - proportion of patients with a =50% reduction in bone marrow mast cells or no aggregates for patients with aggregates at Baseline Additional Secondary Assess change in: - measures of mast cell burden in each treatment cohort (serum tryptase, KIT D816V allele burden in blood, bone marrow mast cells) - best supportive care usage for SM symptoms Assess change in other Patient-Reported Outcomes and Quality of Life measures Assess the safety and tolerability of avapritinib, as assessed by AEs, vital signs, electrocardiograms, and laboratory tests Assess the PK of avapritinib (Part 1 and 2 only);Primary end point(s): Part 1 •The RP2D in patients with ISM. Part 2 •Proportion of responders, defined as =30% reduction in ISM-SAF TSS, from Baseline to C7D1. Part 3 •The long-term safety and efficacy of avapritinib. ;Timepoint(s) of evaluation of this end point: Part 1 - weekly for the first 4 weeks, then every 4 weeks Part 2 - Patients will be assessed every 4 weeks through C7D1 Part 3 - All patients in Part 3 will have study visits every 4 weeks until C7D1, then every 8 weeks until C13D1. After C13D1, patients will have visits every 12 weeks for a total study duration of up to 5 years, inclusive of Part 1 and Part 2. | — |
Secondary
| Measure | Time frame |
|---|---|
| Secondary end point(s): Key Secondary (Part 2 Only) • Proportion of patients with a =50% reduction in serum tryptase. • Proportion of patients with a =50% reduction in peripheral blood KIT D816V allele fraction or undetectable (<0.02%) for patients with detectable mutation at Baseline. • Mean change in ISM-SAF TSS. • Proportion of patients with a =50% reduction in bone marrow mast cells or no aggregates for patients with aggregates at Baseline. Additional Secondary • Change in measures of mast cell burden: serum tryptase, KIT D816V allele burden in blood, bone marrow mast cells. • Change in best supportive care usage. • Change in MC-QoL, PGIS, SF-12, PGIC, and EQ-5D-5L. • Safety and tolerability of avapritinib, as assessed by AEs, vital signs, electrocardiograms, and laboratory tests. • Pharmacokinetics of avapritinib (Part 1 and 2 only) ;Timepoint(s) of evaluation of this end point: • Key Secondary (Part 2 Only): from Baseline to C7D1 • KIT D816V & Tryptase: C1D1/D15, C2D1, C4D1 (KIT), every visit through C4D1 (tryptase), every 4w until roll over (Part 1); every cycle through C7D1 (Part 2); every cycle through C7D1, every 8w during C7-13, and every 12w during C13 through EOT (Part 3) • Bone marrow biopsy: Screening, C4D1 (Part 1), C7D1 (Part 2); optional at approx. 1 year after end of Part 1 & 2 biopsy (Part 3) • ISM-SAF: daily through C13D1 in Part 3 • QoL: each visit through C13D1 in Part 3 • AE & BSC: throughout study • Vital signs, hematology & chemistry: every visit until EOT • ECG: Screening, D1 of every cycle (Part 1 & 2); D1 of every visit (Part 3) • Sparse PK: before & after study drug dosing (Part 1 & 2) | — |
Countries
Belgium, Canada, Denmark, Germany, Italy, Netherlands, Spain, Switzerland, United Kingdom, United States
Contacts
Public ContactProject Director, Global Oncology
Syneos Health, LLC
Outcome results
None listed