Advanced Systemic Mastocytosis (AdvSM) MedDRA version: 20.0 Level: LLT Classification code 10056453 Term: Aggressive systemic mastocytosis System Organ Class: 100000004864
Conditions
Sponsors
Blueprint Medicines Corporation
Eligibility
Sex/Gender
All
Inclusion criteria
Inclusion criteria: 1. Patients who are = 18 years of age. 2. Patients must have 1 of the following diagnoses as confirmed by WHO diagnostic criteria (Appendix 4, Appendix 5, and Appendix 6). Before enrollment, the SSC must confirm the diagnosis of AdvSM (based on Central Pathology Laboratory assessment of BM). o ASM. o SM-AHN. The AHN must be myeloid, with the following exceptions that are excluded: • AML. • Myelodysplastic syndrome that is very high- or high-risk, as defined by the International Prognostic Scoring System for Myelodysplastic Syndromes (Greenberg et al, 2012). • A myeloid AHN with = 10% BM or PB blasts. • Philadelphia chromosome-positive malignancies. Incidental indolent, low-grade lymphoid AHNs (eg, chronic lymphocytic leukemia) not requiring treatment are eligible. o MCL, including diagnoses with an AHN component. 3. Patients with SM-AHN should have received prior treatment for the AHN component of disease if, in the opinion of the Investigator, such therapy was appropriate. 4. Patient must have a BM biopsy taken within 56 days of C1D1, assessed by the Central Pathology Laboratory. 5. Cohort 1 only: Patient must have at least 1 of the following measurable C-findings, per modified IWG-MRT-ECNM criteria, attributed to SM (Appendix 6, unless diagnosis is MCL, which does not require a C-finding). Laboratory abnormality C-findings should not be assessed until the required washout period from last cytoreductive therapy has been met. If a C-finding improves during the Screening period, prior to dosing, and no longer meets criteria for evaluability, it can no longer be counted as a C-finding. In addition, • Patients must have documented evidence of mast cell aggregates in the bone marrow or other extracutaneous organ based on central pathology. • Patient must be willing to have follow up biopsies of affected organ(s) to document response. Measurable C-findings: o Cytopenias: • ANC 1.5 × upper limit of normal [ULN]), aspartate aminotransferase (AST; > 3.0 × ULN), alanine aminotransferase (ALT; > 3.0 × ULN), or alkaline phosphatase (> 2.5 × ULN) with 1 of the following present: • Ascites or • Clinically relevant portal hypertension or • Liver MC infiltration that is biopsy-proven or • No other identified cause of abnormal liver function. o = Grade 2 hypoalbuminemia (< 3.0 g/dL). o A spleen that is palpable = 5 cm below the left costal margin. o Transfusion-dependent anemia defined as: • Transfusion of = 6 units packed red blood cells (PRBCs) in the 12 weeks before C1D-8 and • Most recent transfusion occurring during the 4 weeks before C1D-8 and • Transfusion administered for hemoglobin = 8.5 g/dL and • Reason for transfusion is not bleeding, hemolysis, or therapy-related. 6. Patient must have a serum tryptase = 20 ng/mL. 7. Patients receiving cytoreductive therapy within the preceding 12 weeks must have discontinued therapy due to disease progression, refractory disease, lack of efficacy, or intoleran
Exclusion criteria
Exclusion criteria: 1. Patient has received prior treatment with avapritinib. 2. Patient has received any cytoreductive therapy (including midostaurin and other TKIs, hydroxyurea, azacitidine) or an investigational agent less than 14 days, and for cladribine, interferon alpha, pegylated interferon and any antibody therapy (eg, brentuximab vedotin) less than 28 days before obtaining screening BM biopsy for this study. If the patient has progressive disease and it is in the patient’s best interest to enroll in the study rapidly, cytoreductive therapy may be discontinued 1 day before the screening BM biopsy with approval from the Medical Monitor. Cytoreductive therapy may not be restarted during Screening or while on study. 3. Patient has received prior radiotherapy within 14 days before the screening BM biopsy, unless given to palliate specific sites of disease (eg, bone lesion). 4. Patient received any hematopoietic growth factor within 14 days of screening BM biopsy. 5. Patient requires therapy with a concomitant medication that is a strong inhibitor, strong inducer, or moderate inducer of CYP3A4 (Appendix 13). 6. Patient has had a major surgical procedure within 14 days of the first dose of study drug. Surgical procedures such as central venous catheter placement, BM biopsy, and feeding tube placement are considered minor surgical procedures. 7. Patient is a candidate for allogeneic hematopoietic stem cell transplantation for treatment of SM, in the opinion of the Investigator. 8. Patient has eosinophilia and known positivity for the FIP1L1-PGDFRA fusion, unless the patient has demonstrated relapse or PD on prior imatinib therapy. Patients with eosinophilia (> 1.5 × 10^9/L), who do not have a detectable KIT D816 mutation, must be tested for a PDGFRA fusion mutation by fluorescence in situ hybridization (FISH) or PCR. 9. Patient has history of another primary malignancy that has been diagnosed or required therapy within 3 years before the first dose of study drug. 10. Patient meets any of the following laboratory criteria: o AST or ALT > 3.0 × ULN; no restriction if due to suspected liver infiltration by MCs. o Bilirubin > 1.5 × ULN; no restriction if due to suspected liver infiltration by MCs or Gilbert’s disease. (In the case of Gilbert’s disease, a direct bilirubin > 2.0 × ULN would be an exclusion.) o Estimated glomerular filtration rate (eGFR) 1.5 × ULN. oPlatelet count 480 msec. 12. Patient has a history of a seizure disorder (eg, epilepsy) or requirement for antiseizure medication. 13. Patient has a history of a cerebrovascular accident or transient ischemic attacks within 1 year before the first dose of study drug. 14. Patient has a known risk or recent history (12 months before the first dose of study drug) of intracranial bleeding (eg, brain aneurysm, concomitant vitamin K antagonist use). 15. Patient has a primary brain malignancy or metastases to the brain. 16. Patient has clinically significant, uncontrolled cardiovascular disease, including Grade III or IV congestive heart failure according to the New York Heart Association classification; myocardial infarction or unstable angina within the previous 6 months; clinically significant, uncontrolled arrhythmias; or uncontrolled hypertension. 17. Patient is unwilling or unable to comply wit
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Main Objective: The primary objective is to determine adjudicated ORR (CR/ CRh + PR + CI) based on modified IWG-MRT-ECNM consensus response criteria in patients with AdvSM treated with avapritinib and enrolled in Cohort 1.;Secondary Objective: Key secondary objective: Assess mean change from baseline in AdvSM-SAF TSS Additional secondary objectives • Determine local investigator determined ORR based on modified IWG-MRT-ECNM response criteria, using C-findings when present at baseline • Determine time-to-event outcomes including time-to-response (TTR), DOR, PFS, and OS • Determine morphologic response (CR/CRh+ PR) based on Pure Pathological Response criteria. • Determine ORR and other clinical outcome measures (DOR, PFS, OS) analyzed by prior therapy and by genotype • Assess changes in the following individual measures of MC burden: BM MCs, serum tryptase, KIT mutation burden in PB and BM, liver and spleen volume by imaging • Assess additional PROs using the AdvSM-SAF and changes in QoL measures • Assess safety and PK of avapritinib • Correlate avapritinib exposure with safety and efficacy endpoints;Primary end point(s): Adjudicated ORR (CR/CRh + PR + CI) based on modified IWG-MRT-ECNM criteria, confirmed 12 weeks after initial response in patients in Cohort 1 only.;Timepoint(s) of evaluation of this end point: At C1D15, C2D1, C3D1, C7D1 and C11D1 and then every 6 cycles. Also performed 12 weeks (± 4 weeks) after documentation of CR or PR to confirm response and 4 weeks after SM and/or AHN PD or clinical progression to confirm PD. Performed at EOT if patient discontinues for reasons other than PD or initiation of alternative cytoreductive therapy. | — |
Secondary
| Measure | Time frame |
|---|---|
| Secondary end point(s): • Mean change from baseline in AdvSM-SAF TSS in patients in Cohorts 1 and 2. Additional secondary endpoints for patients in Cohorts 1 and 2: • Local Investigator assessed ORR (CR/CRh + PR + CI) based on modified IWG MRT ECNM criteria, using C-findings when present, confirmed 12 weeks after initial response. • Objective response rate (CR/CRh + PR) based on Pure Pathological Response criteria • Time-to-event outcomes including TTR, DOR, PFS, and OS. • CR/CRh + PR and clinical benefit (CR/CRh + PR + CI + SD) based on modified IWG-MRT-ECNM criteria. • Overall response rate and other clinical outcome measures (DOR, PFS, OS) analyzed by prior therapy and by genotype. • Changes in BM MCs, serum tryptase, KIT mutation burden (eg, D816V) in PB and BM, and liver and spleen volume by imaging. • Mean change from baseline in AdvSM-SAF domain and individual symptom scores. • Changes in PGIS and EORTC QLQ-C30 (global health status, functional scales, and symptom scales/items) score. • Safety of avapritinib, as assessed by AEs, changes in vital signs, ECGs, and laboratory testing. • PK of avapritinib. • Correlations between avapritinib exposure and safety and efficacy endpoints.;Timepoint(s) of evaluation of this end point: •AdvSM-SAF: daily from C1D7 to C17 or until pt stops •OS: until death or loss to F/U •BM biopsy/aspirate: screening, C3D1, C7D1, C11D1, every 6 cycles, EoT, PD F/U •Serum tryptase: screening, C1D15, C2D1, C3D1, C7D1, C11D1, every 6 cycles, EoT, PD F/U •Liver/spleen imaging: screening, C3D1, C7D1, C11D1, every 6 cycles, EoT •KIT D816V mutant allele burden: screening, C1D1/D15, C2D1, C3D1, C7D1, C11D1, every 6 cycles, EoT, PD F/U •Resp: C1D15, C2D1, C3D1, C7D1, C11D1, every 6 cycles, EoT, PD F/U •PGIS, EORTC-QLQ-C30: each visit through C17, EoT •AE: from C1D1 to Safety F/U •Vital signs, ECG: each visit through EoT •Lab: screening, each visit from C1D15 to EoT, PD F/U •Std PK: C1D1/D15, C2D1, C3D1, C5D1 •Intensive PK (subset of 15 pts): C1D1 | — |
Countries
Austria, Canada, Denmark, France, Germany, Italy, Netherlands, Norway, Poland, Spain, United Kingdom, United States
Contacts
Public ContactProject Director, Global Oncology
Syneos Health, LLC
Outcome results
None listed