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

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Blueprint Medicines Corp.

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Hemic and Lymphatic Diseases [C15]

Trial duration

29 Mar 2023 → 11 Mar 2025

Decision date (initial)

2024-04-15

Transition trial

Yes

Low-intervention

No

Rare-disease indication

Yes

Vulnerable population

Yes

Funding sources

Blueprint Medicines Corporation

External identifiers

EU CT number

2023-510144-20-00

EudraCT number

2022-001535-87

ClinicalTrials.gov

NCT05609942

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Pharmacokinetic, Efficacy, Dose response, Pharmacodynamic, Therapy, Others

Monotherapy (Arm 1) - Primary Objectives (Dose Escalation): To determine the RD for BLU-263 monotherapy
Monotherapy (Arm 1) - Primary Objectives (Dose Escalation & Expansion): To assess the safety and tolerability of BLU-263 monotherapy; and To assess clinical efficacy of BLU-263 given as monotherapy at the RD to patients with AdvSM
Combination (Arm 2) - Primary Objectives (Dose Escalation): To determine the RD for BLU-263 in combination with azacitidine in patients with SM-AHN; and To assess the safety and tolerability of BLU-263 in combination with azacitidine
Combination (Arm 2) - Primary Objectives (Dose Expansion): To assess the safety and tolerability of BLU-263 in combination with azacitidine

Secondary objectives 1

1. Monotherapy (Arm 1) (Dose Escalation & Expansion): -To assess the ORR -To characterize the PK profile of BLU-263 when given as monotherapy -To determine the OS of patients with AdvSM treated with BLU-263 - To assess additional measures of clinical efficacy of BLU-263 given as monotherapy Combination (Arm 2): -To assess the ORR -To assess the PPR rate for SM of BLU-263 given in combination with azacitidine - To assess the PK of BLU-263 and azacitidine when given alone and in combination

Conditions and MedDRA coding

Advanced Systemic Mastocytosis

Study design 2 periods

Regulatory references

EMA paediatric investigation plan (PIP)

EMEA-003269-PIP01-22

Plan to share IPD

No

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 1

1. Key Inclusion Criteria : - 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: 1. Aggressive SM (ASM). 2. 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. 3. Mast cell leukemia (MCL), including diagnoses with an AHN component, that does not require a C-finding. 4. 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). Arm 2 (Combination Therapy): A2_1. For Arm 2, patients must have an SM-AHN diagnoses, based on WHO diagnostic criteria. Diagnosis of the AHN component of SM-AHN must be confirmed based on the central pathology laboratory assessment of the BM. Upon discussion with the Sponsor hematologic neoplasms which are felt to have strong rationale to consider the combination treatment of BLU-263 and HMA may be considered for enrollment.

Exclusion criteria 1

1. Key Exclusion Criteria: - 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. Arm 2 (Combination Therapy): A2_1. Intermediate, low, or very low risk MDS. A2_2. Known hypersensitivity to azacitidine or any of their ingredients. A2_3. Platelet count < 75 x 109/L (within 4 weeks of the first dose of study drug) or receiving platelet transfusions or TPO-RA within the prior 14 days.

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 3

1. Monotherapy (Arm 1) (Dose Escalation): - The RD will be primarily determined by the number of DLTs in the first 28 days of treatment with BLU-263 monotherapy. Monotherapy (Arm 1) (Dose Escalation & Expansion): - Safety profile of BLU-263, as assessed by the type, frequency, severity, timing, and relationship to study drug of any AEs or SAEs, and changes in vital signs, ECGs, and safety laboratory tests - Pure pathological response rate for SM in selective KIT inhibitor-naïve patients
2. Combination (Arm 2) (Dose Escalation): - 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 - Safety profile of BLU-263, as assessed by the type, frequency, severity, timing, and relationship to study drug of any AEs or SAEs, and changes in vital signs, ECGs, and safety laboratory tests
3. Combination (Arm 2) (Dose Expansion): - Safety profile of BLU-263, as assessed by the type, frequency, severity, timing, and relationship to study drug of any AEs or SAEs, and changes in vital signs, ECGs, and safety laboratory tests, frequency, severity, timing, and relationship to study drug of any AEs or SAEs, and changes in vital signs, ECGs, and safety laboratory tests

Secondary endpoints 2

1. Monotherapy (Arm 1) (Dose Escalation & Expansion): - Overall response rate for AdvSM, using mIWG MRT-ECNM - Pharmacokinetic parameters of BLU-263,including Cmax, Tmax, AUC0-24, Vz/F, t½, CL/F, and accumulation ratio - Overall survival - Time-to-response, DOR, and PFS - Proportion of patients pursuing stem cell transplant
2. Combination (Arm 2) : - Overall response rate for SM, using mIWG-MRT-ECNM - Pure pathological response rate for SM - Pharmacokinetic parameters of BLU-263 and azacitidine including: Cmax, Tmax, AUC0-24, Vz/F, t½, CL/F, and accumulation ratio

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 3

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Blueprint Medicines Corp.

Sponsor organisation

Blueprint Medicines Corp.

Address

45 Sidney Street

City

Cambridge

Postcode

02139-4133

Country

United States

Scientific contact point

Organisation

Blueprint Medicines Corp.

Contact name

Medical Information

Public contact point

Organisation

Blueprint Medicines Corp.

Contact name

Medical Information

Third parties 11

Locations

6 EU/EEA countries · 8 investigational sites

By country

Investigational sites

Country notifications

Trial-start, recruitment-start, end and early-termination notifications submitted per Member State

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Summary of results Art. 37(4) CTR

Layperson summary Annex V

Documents 11 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

2 submissions — initial application plus substantial / non-substantial modifications