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JOURNAL ONKOLOGIE – STUDIE
AZURE

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

Rekrutierend

NCT-Nummer:
NCT05609942

Studienbeginn:
September 2023

Letztes Update:
02.04.2024

Wirkstoff:
BLU-263, azacitidine

Indikation (Clinical Trials):
Hematologic Neoplasms, Mastocytosis, Mastocytosis, Systemic

Geschlecht:
Alle

Altersgruppe:
Erwachsene (18+)

Phase:
-

Sponsor:
Blueprint Medicines Corporation

Collaborator:
-

Kontakt

Studienlocations
(3 von 11)

University Medical Centre Mannheim
68167 Mannheim
(Baden-Württemberg)
GermanyRekrutierend» Google-Maps
Stanford Cancer Institute
94305 Palo Alto
United StatesNoch nicht rekrutierend» Google-Maps
Dana-Farber Cancer Institute
02215 Boston
United StatesRekrutierend» Google-Maps
University of Michigan
48109 Ann Arbor
United StatesRekrutierend» Google-Maps
Huntsman Cancer Institute
84112 Salt Lake City
United StatesRekrutierend» Google-Maps
CHU Caen - Institut d'Hematologie de Basse Normandie
14033 Caen
FranceRekrutierend» Google-Maps
Maastricht University Medical Center
6229 HX Maastricht
NetherlandsRekrutierend» Google-Maps
Instituto de Estudios de Mastocitosis de Castilla La Mancha (CLMast)
45071 Toledo
SpainRekrutierend» Google-Maps
Alle anzeigen

Studien-Informationen

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).

Ein-/Ausschlusskriterien

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).

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.

Studien-Rationale

Primary outcome:

1. Dose Escalation: Number of Dose-limiting Toxicities (DLTs) (monotherapy only) (Time Frame - 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.

2. Dose Escalation: Number of DLTs (combination therapy only) (Time Frame - 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.

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

4. Dose Escalation and Expansion: Number of Participants with Adverse Events (AEs) (Time Frame - Up to approximately 4 years)

5. Dose Escalation and Expansion: Number of Participants with Serious Adverse Events (SAEs) (Time Frame - Up to approximately 4 years)

Secondary outcome:

1. 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) (Time Frame - Up to approximately 4 years):
ORR is defined as CR + CRh + PR + Clinical Improvement (CI)

2. Dose Escalation and Expansion: ORR for SM Using Modified IWG-MRT-ECNM (combination therapy only) (Time Frame - Up to approximately 4 years)

3. Dose Escalation and Dose Expansion: Maximum Plasma Concentration (Cmax) of BLU-263 (Time Frame - Up to approximately 4 years)

4. Dose Escalation and Dose Expansion: Cmax of Azacitidine (combination therapy only) (Time Frame - Up to approximately 4 years)

5. Dose Escalation and Dose Expansion: Time to Maximum Concentration (Tmax) of BLU-263 (Time Frame - Up to approximately 4 years)

6. Dose Escalation and Dose Expansion: Tmax of Azacitidine (combination therapy only) (Time Frame - Up to approximately 4 years)

7. Dose Escalation and Dose Expansion: Area Under the Curve From Time Zero to 24 Hours (AUC(0-24)) of BLU-263 (Time Frame - Up to approximately 4 years)

8. Dose Escalation and Dose Expansion: AUC(0-24) of Azacitidine (combination therapy only) (Time Frame - Up to approximately 4 years)

9. Dose Escalation and Dose Expansion: Apparent Volume of Distribution (Vz/F) of BLU-263 (Time Frame - Up to approximately 4 years)

10. Dose Escalation and Dose Expansion: Vz/F of Azacitidine (combination therapy only) (Time Frame - Up to approximately 4 years)

11. Dose Escalation and Dose Expansion: Terminal Elimination Half-life (t1/2) of BLU-263 (Time Frame - Up to approximately 4 years)

12. Dose Escalation and Dose Expansion: t1/2 of Azacitidine (combination therapy only) (Time Frame - Up to approximately 4 years)

13. Dose Escalation and Dose Expansion: Apparent Oral Clearance (CL/F) of BLU-263 (Time Frame - Up to approximately 4 years)

14. Dose Escalation and Dose Expansion: CL/F of Azacitidine (combination therapy only) (Time Frame - Up to approximately 4 years)

15. Dose Escalation and Dose Expansion: Accumulation Ratio of BLU-263 (Time Frame - Up to approximately 4 years)

16. Dose Escalation and Dose Expansion: Accumulation Ratio of Azacitidine (combination therapy only) (Time Frame - Up to approximately 4 years)

17. Dose Escalation and Expansion: Overall Survival (OS) (monotherapy only) (Time Frame - Up to approximately 4 years)

18. Dose Escalation and Expansion: Time to Response (TtR) (monotherapy only) (Time Frame - Up to approximately 4 years)

19. Dose Escalation and Expansion: Duration of Response (DOR) (monotherapy only) (Time Frame - Up to approximately 4 years)

20. Dose Escalation and Expansion: Progression-Free Survival (PFS) (monotherapy only) (Time Frame - Up to approximately 4 years)

21. Dose Escalation and Expansion: Proportion of Participants Pursuing Stem Cell Transplant (monotherapy only) (Time Frame - Up to approximately 4 years)

22. Dose Escalation and Expansion: PPR Rate for SM (combination therapy only) (Time Frame - Up to approximately 4 years)

Studien-Arme

  • Experimental: Monotherapy
    Participants with AdvSM (ASM, SM-AHN, or MCL) will receive BLU-263 monotherapy.
  • Experimental: Combination therapy
    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.

Geprüfte Regime

  • BLU-263 (elenestinib):
    BLU-263 Oral Tablets
  • Azacitidine:
    Azacitidine powder for suspension for intravenous infusion / subcutaneous injection

Quelle: ClinicalTrials.gov


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