Study of Elenestinib (BLU-263) in Advanced Systemic Mastocytosis (AdvSM) and and Other KIT Altered Hematologic Malignancies

NCT05609942 | Terminated Phase 1 FDA Drug

• 2 other identifiers: BLU-263-21012022-001535-87
• Study Type: interventional
• Target: 9
• Locations: 7 countries
• Sites: 11

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.

Conditions

Advanced Systemic Mastocytosis

Keywords

BLU-263; elenestinib; azacitidine; AdvSM; KIT D816V; Advanced systemic mastocytosis; Mast cell leukemia; MCL; Systemic mastocytosis; SM; SM-AHN; CMML-2; Myelodysplastic/myeloproliferative neoplasms; MDS/MPN; Myeloid neoplasms; ASM

Outcome Measures

Primary Outcomes (5)

• Dose Escalation: Number of Dose-limiting Toxicities (DLTs) (monotherapy only)

  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.

  28 Days

• Dose Escalation: Number of DLTs (combination therapy only)

  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.

  28 Days

• Dose Escalation and Expansion: Pure Pathological Response (PPR) Rate for SM in Selective KIT Inhibitor-naïve Participants (monotherapy only)

  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)

  Up to approximately 4 years

• Dose Escalation and Expansion: Number of Participants with Adverse Events (AEs)

  Up to approximately 4 years

• Dose Escalation and Expansion: Number of Participants with Serious Adverse Events (SAEs)

  Up to approximately 4 years

Secondary Outcomes (22)

• 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

• 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: Maximum Plasma Concentration (Cmax) of BLU-263

  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: Time to Maximum Concentration (Tmax) of BLU-263

  Up to approximately 4 years

Study Arms (2)

Monotherapy

EXPERIMENTAL

Participants with AdvSM (ASM, SM-AHN, or MCL) will receive BLU-263 monotherapy.

Drug: BLU-263

Combination therapy

EXPERIMENTAL

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.

Drug: BLU-263; Drug: Azacitidine

Interventions

BLU-263 DRUG

BLU-263 Oral Tablets

Also known as: elenestinib

Combination therapy; Monotherapy

Azacitidine DRUG

Azacitidine powder for suspension for intravenous infusion / subcutaneous injection

Combination therapy

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Participant has Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 0-2
• Participant must have a new Bone Marrow (BM) biopsy or may use archival tissue if taken within 56 days prior to C1D1 and participant must be willing to have follow-up BM Biopsies.
• Participants receiving antineoplastic therapy within the preceding 12 weeks must have discontinued therapy due to disease progression, refractory disease, lack of efficacy, or intolerance.
• Participants treated with 1 prior selective KIT inhibitor (such as avapritinib or CGT9486) will be permitted on study after confirmation of KIT D816V mutation and with written approval of the study Sponsor. Participants who discontinued treatment with a prior selective KIT inhibitor due to a severe AE that was thought to be related to prior treatment will not be eligible to participate in the study.
• Arm 1 (Monotherapy): Participants must have one of the following AdvSM diagnoses, based on World Health Organization (WHO) diagnostic criteria.
• Before enrollment, diagnosis of AdvSM must be confirmed based on Central Pathology Laboratory assessment of BM:
• Aggressive SM (ASM).
• SM-AHN that in the opinion of the Investigator is not considered to be a candidate for Hypomethylating agent (HMA) monotherapy. Incidental indolent, low-grade lymphoid AHNs (eg, chronic lymphocytic leukemia) not requiring treatment are eligible.
• Mast cell leukemia (MCL), including diagnoses with an AHN component, that does not require a C-finding.
• Upon discussion with the Sponsor, other relapsed or refractory hematologic neoplasms with evidence of aberrant KIT or PDGFR may be considered for enrollment. (eg, participants with chronic myeloid neoplasms, such as subvariants of MDS/MPN that harbor activating KIT exon 17 mutations but do not fulfill the diagnostic criteria of SM-AHN, and participants with myeloid/lymphoid neoplasms with PDGFRa/b fusion genes and mutations conferring resistance to imatinib, such as T674I or D842V).

You may not qualify if:

• 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 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.

Sponsors & Collaborators

• Blueprint Medicines Corporation: lead

Study Sites (11)

Stanford Cancer Institute

Palo Alto, California, 94305, United States

Location

Dana-Farber Cancer Institute

Boston, Massachusetts, 02215, United States

Location

University of Michigan

Ann Arbor, Michigan, 48109, United States

Location

Huntsman Cancer Institute

Salt Lake City, Utah, 84112, United States

Location

Antwerp University Hospital

Edegem, 2650, Belgium

Location

University Hospital Ghent

Ghent, 9000, Belgium

Location

CHU Caen - Institut d'Hematologie de Basse Normandie

Caen, 14033, France

Location

University Medical Centre Mannheim

Mannheim, 68167, Germany

Location

Maastricht University Medical Center

Maastricht, 6229 HX, Netherlands

Location

Oslo University Hospital

Oslo, 0450, Norway

Location

Instituto de Estudios de Mastocitosis de Castilla La Mancha (CLMast)

Toledo, 45071, Spain

Location

MeSH Terms

Conditions

Mastocytosis, Systemic; Leukemia, Mast-Cell; Myelodysplastic-Myeloproliferative Diseases

Interventions

Azacitidine

Condition Hierarchy (Ancestors)

Mastocytosis; Neoplasms, Connective Tissue; Neoplasms, Connective and Soft Tissue; Neoplasms by Histologic Type; Neoplasms; Mast Cell Activation Disorders; Immune System Diseases; Leukemia; Leukemia, Myeloid, Acute; Leukemia, Myeloid; Hematologic Diseases; Hemic and Lymphatic Diseases; Bone Marrow Diseases

Intervention Hierarchy (Ancestors)

Aza Compounds; Organic Chemicals; Cytidine; Pyrimidine Nucleosides; Pyrimidines; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Nucleosides; Nucleic Acids, Nucleotides, and Nucleosides; Ribonucleosides

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SEQUENTIAL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: November 2, 2022
• First Posted: November 8, 2022
• Study Start: September 25, 2023
• Primary Completion: January 14, 2025
• Study Completion: March 10, 2025
• Last Updated: April 10, 2025

Record last verified: 2025-03

Data Sharing

• IPD Sharing: Will not share

Locations

US (4); BE (2); DE (1); NL (1); NO (1); ES (1); FR (1)