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

Sponsor

Blueprint Medicines Corporation (Industry)

Overall Status

Not yet recruiting

CT.gov ID

NCT05609942

Collaborator

(none)

108

Enrollment

Arms

59.1

Anticipated Duration (Months)

Study Details

Study Description

Brief Summary

The goal of this clinical trial is to evaluate BLU-263 in participants with Advanced Systemic Mastocytosis (AdvSM), SM-Associated hematologic neoplasm (SM-AHN), and other hematologic malignancies. The main questions it aims to answer are:

Determine Recommended Dose of BLU-263 monotherapy for participants with AdvSM
Safety and tolerability of BLU-263 monotherapy
Efficacy of BLU-263 monotherapy in participants with AdvSM
Determine Recommended Dose of BLU-263 in combination with azacitidine in participants with AdvSM
Safety and tolerability of BLU-263 in combination with azacitidine
Efficacy of 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.

Condition or Disease	Intervention/Treatment	Phase
Advanced Systemic Mastocytosis	Drug: BLU-263 Drug: Azacitidine	Phase 1/Phase 2

Detailed Description

Systemic mastocytosis includes five major subtypes: Indolent SM (ISM), SM with an associated hematologic neoplasm of non-MC lineage (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).

Study Design

Study Type:

Interventional

Anticipated Enrollment :

108 participants

Allocation:

Non-Randomized

Intervention Model:

Sequential Assignment

Masking:

None (Open Label)

Primary Purpose:

Treatment

Official Title:

A Phase 1/2, Open-label, 2-arm Study Evaluating BLU-263 as Monotherapy and in Combination With Azacitidine, in Patients With KIT Altered Hematologic Malignancies

Anticipated Study Start Date :

Dec 1, 2022

Anticipated Primary Completion Date :

Nov 5, 2027

Anticipated Study Completion Date :

Nov 5, 2027

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Monotherapy Participants with AdvSM (ASM, SM-AHN, or MCL) will receive BLU-263 monotherapy.	Drug: BLU-263 BLU-263 Oral Tablets
Experimental: Combination therapy Participants with high risk and very high risk systemic mastocytosis with an associated hematologic neoplasm of non-MC lineage (SM-AHN) will receive BLU-263 in combination with azacitidine.	Drug: BLU-263 BLU-263 Oral Tablets Drug: Azacitidine Azacitidine powder for suspension for intravenous infusion / subcutaneous injection

Arm

Intervention/Treatment

Experimental: Monotherapy

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

Drug: BLU-263

BLU-263 Oral Tablets

Experimental: Combination therapy

Participants with high risk and very high risk systemic mastocytosis with an associated hematologic neoplasm of non-MC lineage (SM-AHN) will receive BLU-263 in combination with azacitidine.

Drug: BLU-263

BLU-263 Oral Tablets

Drug: Azacitidine

Azacitidine powder for suspension for intravenous infusion / subcutaneous injection

Outcome Measures

Primary Outcome Measures

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 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 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]
Dose Escalation and Expansion: Number of Participants with Serious Adverse Events (SAEs) [Up to approximately 4 years]

Secondary Outcome Measures

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: 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]
Dose Escalation and Dose Expansion: Tmax 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: AUC(0-24) of Azacitidine (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: Vz/F of Azacitidine (combination therapy only) [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: t1/2 of Azacitidine (combination therapy only) [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 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 Dose Expansion: Accumulation Ratio 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 Expansion: Time to Response (TtR) (monotherapy only) [Up to approximately 4 years]
Dose Escalation and Expansion: Duration of Response (DOR) (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: Proportion of Participants Pursuing Stem Cell Transplant (monotherapy only) [Up to approximately 4 years]
Dose Escalation and Expansion: PPR Rate for SM (combination therapy only) [Up to approximately 4 years]

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Key Inclusion Criteria :

Participant has Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 0-3
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.

Arm 1 (Monotherapy): Participants must have one of the following AdvSM diagnoses, based on World Health Organization (WHO) diagnostic criteria.

Before enrollment, the Central Pathology Laboratory must confirm the diagnosis of AdvSM (based on Central Pathology Laboratory assessment of BM):

Aggressive SM (ASM).
SM-AHN which 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, which does not require a C-finding.
Upon discussion with the sponsor, other relapsed or refractory, potentially BLU-263-responsive hematologic neoplasms (e.g., those with evidence of aberrant KIT) may be considered for enrollment.

Key Exclusion Criteria:

Diagnosis of a Philadelphia chromosome positive malignancy
Acute myeloid leukemia.
If the patient 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.
Patient has received hydroxyurea within 7 days prior to the first dose of BLU-263.
Participant received prior HMA therapy (e.g., azacitidine, decitabine) for the current diagnosis.
Patient must not be eligible for allogenic hematopoietic stem cell transplantation.
Patient 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 PLX-9486 (bezuclastinib)).

Arm 1 (Monotherapy):

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.