Study of Elenestinib (BLU-263) in Advanced Systemic Mastocytosis (AdvSM) and and Other KIT Altered Hematologic Malignancies
- Conditions
- Advanced Systemic Mastocytosis
- Interventions
- Registration Number
- NCT05609942
- Lead Sponsor
- Blueprint Medicines Corporation
- Brief Summary
The goal of this clinical trial is to evaluate elenestinib (BLU-263) in participants with Advanced Systemic Mastocytosis (AdvSM), SM with an associated hematologic neoplasm (SM-AHN), and other hematologic malignancies. The main questions it aims to answer are:
* Determine Recommended Dose of elenestinib (BLU-263) monotherapy for participants with AdvSM
* Safety and tolerability of elenestinib (BLU-263) monotherapy
* Efficacy of elenestinib (BLU-263) monotherapy in participants with AdvSM
* Determine Recommended Dose of elenestinib (BLU-263) in combination with azacitidine in participants with AdvSM
* Safety and tolerability of elenestinib (BLU-263) in combination with azacitidine
* Efficacy of elenestinib (BLU-263) in combination with azacitidine in participants with AdvSM
The estimated study duration for each participant will be approximately 4 years: 2 years of treatment followed by 2 years of follow-up. Participants may be required to attend monthly visits for the first six months, followed by quarterly visits for the remainder of the study.
- Detailed Description
Systemic mastocytosis includes five major subtypes: Indolent SM (ISM), SM with an associated hematologic neoplasm (SM-AHN), aggressive SM (ASM), and MC leukemia (MCL). In 2016, the smoldering subtype of SM, a former provisional ISM subvariant, was designated as a distinct variant of SM by the World Health Organization (WHO). Aggressive SM, SM-AHN, and MCL together are referred to as Advanced SM (AdvSM).
Recruitment & Eligibility
- Status
- TERMINATED
- Sex
- All
- Target Recruitment
- 9
Not provided
- Diagnosis of a Philadelphia chromosome positive malignancy
- Acute myeloid leukemia.
- If the participant is receiving corticosteroids, and the dose has not been stable for ≥7 days.
- Within the 14 days prior to enrollment, participant has received any antineoplastic therapy (including midostaurin, avapritinib and other tyrosine kinase inhibitors [TKIs]) or an investigational agent.
- Participant has received hydroxyurea within 7 days prior to the first dose of elenestinib (BLU-263).
- Participant received prior HMA therapy (e.g., azacitidine, decitabine) for the current diagnosis.
- Participant must not be eligible for allogenic hematopoietic stem cell transplantation.
- Participant received prior radiotherapy within 14 days of screening BM biopsy.
- Participant received any hematopoietic growth factor (except erythropoietin) within 14 days of screening BM biopsy, or requiring growth factors to maintain adequate neutrophil or platelet levels.
Those participants maintained on a chronic dose of erythropoietin, whose hemoglobin is stable, and dose of erythropoietin has not been changed in the prior 28 days are allowed on study.
- Participant received >1 prior selective KIT inhibitor (eg: avapritinib or bezuclastinib).
- Participant have any of the following laboratory abnormalities on last laboratory assessment within 14 days prior to the first dose of initiation of study drug: a. Alanine aminotransferase and aspartate aminotransferase > 3 × ULN; > 5 × ULN if associated with clinically suspected liver infiltration by mastocytosis or another disease for which the patient enrolled into the study b. Total bilirubin > 1.5 × ULN; > 3 × ULN if associated with liver infiltration by the disease being treated or in the presence of Gilbert's Disease. (In the case of Gilbert's disease, a direct bilirubin > 2.0 ULN would be an exclusion) c. Estimated (Cockcroft-Gault formula) or measured creatinine clearance < 40 mL/min d. Absolute neutrophil count < 0.5 × 10^9/L
- Participant has had a major surgical procedure within 14 days of the first dose of study drug.
- History of another primary malignancy that has been diagnosed or required therapy within 1 year prior to the first dose of study drug. The following are exempt from the 1-year limit: completely resected basal cell and squamous cell skin cancer, curatively treated localized prostate cancer, GI stromal tumor, and completely resected carcinoma in situ of any site.
- Mean resting QTcF > 480 msec, a history of prolonged QT syndrome or Torsades de pointes, or a familial history of prolonged QT syndrome.
- Clinically significant, uncontrolled, cardiovascular disease.
Arm 1 (Monotherapy):
- Myelodysplastic Syndrome (MDS) that is very high- or high-risk as defined by the International Prognostic Scoring System for Myelodysplastic Syndromes-Revised (IPSS-R).
- A myeloid AHN with ≥10% BM or peripheral blood blasts.
- Platelet count <50 x 10^9/L (within 4 weeks prior to the first dose of study drug) or receiving platelet transfusions or thrombopoietin receptor agonists (TPO-RA) within the prior 14 days.
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- SEQUENTIAL
- Arm && Interventions
Group Intervention Description Combination therapy BLU-263 Participants with high risk and very high risk systemic mastocytosis with an associated hematologic neoplasm (SM-AHN) of non-MC lineage will receive BLU-263 in combination with azacitidine. Monotherapy BLU-263 Participants with AdvSM (ASM, SM-AHN, or MCL) will receive BLU-263 monotherapy. Combination therapy Azacitidine Participants with high risk and very high risk systemic mastocytosis with an associated hematologic neoplasm (SM-AHN) of non-MC lineage will receive BLU-263 in combination with azacitidine.
- Primary Outcome Measures
Name Time Method Dose Escalation and Expansion: Number of Participants with Serious Adverse Events (SAEs) Up to approximately 4 years Dose Escalation: Number of Dose-limiting Toxicities (DLTs) (monotherapy only) 28 Days Monotherapy: The Recommended Dose (RD) will be primarily determined by the number of DLTs in the first 28 days of treatment with elenestinib (BLU-263) monotherapy.
Dose Escalation: Number of DLTs (combination therapy only) 28 Days Combination therapy: The RD will be primarily determined by the number of DLTs (during 28 days starting from Day 15 of C1 or Day 15 of C2) with elenestinib (BLU-263) in combination with azacitidine.
Dose Escalation and Expansion: Pure Pathological Response (PPR) Rate for SM in Selective KIT Inhibitor-naïve Participants (monotherapy only) Up to approximately 4 years PPR Rate is defined as complete remission (resolution of palpable splenomegaly/hepatomegaly) (CR) + complete remission with partial recovery of peripheral blood counts (CRh) + partial remission (≥35% reduction in spleen volume) (PR)
Dose Escalation and Expansion: Number of Participants with Adverse Events (AEs) Up to approximately 4 years
- Secondary Outcome Measures
Name Time Method Dose Escalation and Dose Expansion: t1/2 of Azacitidine (combination therapy only) Up to approximately 4 years Dose Escalation and Dose Expansion: Maximum Plasma Concentration (Cmax) of BLU-263 Up to approximately 4 years Dose Escalation and Dose Expansion: Time to Maximum Concentration (Tmax) of BLU-263 Up to approximately 4 years Dose Escalation and Expansion: Overall Response Rate (ORR) for AdvSM using modified International Working Group-Myeloproliferative Neoplasms Research and Treatment and European Competence Network on Mastocytosis (IWG-MRT-ECNM) (monotherapy only) Up to approximately 4 years ORR is defined as CR + CRh + PR + Clinical Improvement (CI)
Dose Escalation and Expansion: ORR for SM Using Modified IWG-MRT-ECNM (combination therapy only) Up to approximately 4 years Dose Escalation and Dose Expansion: Cmax of Azacitidine (combination therapy only) Up to approximately 4 years Dose Escalation and Dose Expansion: Area Under the Curve From Time Zero to 24 Hours (AUC(0-24)) of BLU-263 Up to approximately 4 years Dose Escalation and Dose Expansion: Terminal Elimination Half-life (t1/2) of BLU-263 Up to approximately 4 years Dose Escalation and Dose Expansion: CL/F of Azacitidine (combination therapy only) Up to approximately 4 years Dose Escalation and Dose Expansion: Accumulation Ratio of BLU-263 Up to approximately 4 years Dose Escalation and Expansion: Time to Response (TtR) (monotherapy only) Up to approximately 4 years Dose Escalation and Expansion: Progression-Free Survival (PFS) (monotherapy only) Up to approximately 4 years Dose Escalation and Expansion: PPR Rate for SM (combination therapy only) Up to approximately 4 years Dose Escalation and Dose Expansion: Apparent Volume of Distribution (Vz/F) of BLU-263 Up to approximately 4 years Dose Escalation and Dose Expansion: Apparent Oral Clearance (CL/F) of BLU-263 Up to approximately 4 years Dose Escalation and Expansion: Duration of Response (DOR) (monotherapy only) Up to approximately 4 years Dose Escalation and Expansion: Proportion of Participants Pursuing Stem Cell Transplant (monotherapy only) Up to approximately 4 years Dose Escalation and Dose Expansion: Tmax of Azacitidine (combination therapy only) Up to approximately 4 years Dose Escalation and Dose Expansion: Vz/F of Azacitidine (combination therapy only) Up to approximately 4 years Dose Escalation and Dose Expansion: AUC(0-24) of Azacitidine (combination therapy only) Up to approximately 4 years Dose Escalation and Expansion: Overall Survival (OS) (monotherapy only) Up to approximately 4 years Dose Escalation and Dose Expansion: Accumulation Ratio of Azacitidine (combination therapy only) Up to approximately 4 years
Trial Locations
- Locations (22)
Dana-Farber Cancer Institute
🇺🇸Boston, Massachusetts, United States
University Medical Centre Mannheim
🇩🇪Mannheim, Germany
Stanford Cancer Institute
🇺🇸Palo Alto, California, United States
University of Michigan
🇺🇸Ann Arbor, Michigan, United States
Antwerp University Hospital
🇧🇪Edegem, Belgium
Huntsman Cancer Institute
🇺🇸Salt Lake City, Utah, United States
University Hospital Ghent
🇧🇪Ghent, Belgium
CHU Caen - Institut d'Hematologie de Basse Normandie
🇫🇷Caen, France
Oslo University Hospital
🇳🇴Oslo, Norway
Maastricht University Medical Center
🇳🇱Maastricht, Netherlands
Instituto de Estudios de Mastocitosis de Castilla La Mancha (CLMast)
🇪🇸Toledo, Spain
Stanford Cancer Institute
🇺🇸Palo Alto, California, United States
Dana-Farber Cancer Institute
🇺🇸Boston, Massachusetts, United States
University of Michigan
🇺🇸Ann Arbor, Michigan, United States
Huntsman Cancer Institute
🇺🇸Salt Lake City, Utah, United States
Antwerp University Hospital
🇧🇪Edegem, Belgium
University Hospital Ghent
🇧🇪Ghent, Belgium
CHU Caen - Institut d'Hematologie de Basse Normandie
🇫🇷Caen, France
University Medical Centre Mannheim
🇩🇪Mannheim, Germany
Maastricht University Medical Center
🇳🇱Maastricht, Netherlands
Oslo University Hospital
🇳🇴Oslo, Norway
Instituto de Estudios de Mastocitosis de Castilla La Mancha (CLMast)
🇪🇸Toledo, Spain