Study to assess the safety and efficacy of BLU-263 in patients with indolent and systemic mastocytosis
Zusammenfassung der Studie
This study was designed to determine the recommended dose (RD) of Elenestinib and to assess the safety and efficacy in patients with indolent systemic mastocytosis (ISM), smoldering systemic mastocytosis (SSM), or patients with a mast cell activation syndrome (MCAS). The study consists of five parts and two optional open pharmacokinetics (PK) groups: • Part 1 of the study includes 3 dose groups and a placebo group to determine the RD of Elenestinib in patients with ISM. • Part 2 of the study assesses whether treatment with Elenestinib in addition to the best supportive care (BSC) improves outcomes in patients with ISM compared to placebo + BSC. Part 2 allows up to 99 patients with lower TSS values. • Part 3 of the study is an open extension to further characterize the long-term safety and efficacy of Elenestinib. Patients transition from Part 1 and Part 2 to Part 3 of the study. • Part S will investigate treatment with Elenestinib + BSC in patients with SSM in an open study design. • Part M will investigate treatment with Elenestinib in patients with mMCAS in an open design. • An optional PK group of up to 20 patients may be enrolled before and/or parallel to Part 1. An additional optional PK group of up to 20 patients may also be enrolled before Part 2. Both PK groups aim to better characterize the pharmacokinetics (PK) of Elenestinib in patients with ISM. Patients in the optional PK group(s) may have a wider range of TSS values than the randomized parts of the study or have selected comorbidities or concomitant medications that may influence Elenestinib.
(BASEC)
Untersuchte Intervention
This randomized, double-blind, placebo-controlled phase 2/3 study of Elenestinib in indolent systemic mastocytosis is being conducted to determine the recommended dose (RD) of Elenestinib (Part 1); to assess safety and efficacy compared to placebo in conjunction with the best supportive care (BSC) (Part 2); and to further characterize the safety and efficacy of long-term treatment with Elenestinib (Part 3). Part S will investigate treatment with Elenestinib + BSC in patients with SSM in an open study design. Part M of the study will investigate treatment with Elenestinib in patients with a mast cell activation syndrome (MCAS) in an open design. And two optional PK groups aim to better characterize the pharmacokinetics (PK) of Elenestinib in patients with ISM.
(BASEC)
Untersuchte Krankheit(en)
Indolent and smoldering systemic mastocytosis. Systemic mastocytosis (SM) is a clonal neoplastic mast cell (MC) disorder characterized by an increased MC burden with focal and/or diffuse infiltrates of neoplastic MC in the skin, bone marrow (BM), spleen, liver, gastrointestinal (GI) tract, and other organs, and an increased release of MC mediators. The bone marrow is involved in all patients. The World Health Organization (WHO) has developed criteria for the diagnosis and classification of SM. In the most recent update provided by the WHO, SM is classified into indolent SM (ISM), smoldering SM (SSM), systemic mastocytosis with associated clonal hematological disease not attributable to the mast cell lineage (SM AHN), aggressive SM (ASM), and mast cell leukemia (MCL).
(BASEC)
1. The patient must be ≥18 years of age at the time of signing the informed consent. (Patients aged ≥16 and <18 years also have the option to participate in the study) 2. The patient must have an Eastern Cooperative Oncology Group (ECOG PS) performance status of 0 to 2. 3. In Part 1, the patient must have an average TSS of at least 14 days of ≥ 28 and additionally ≥ 1 symptom in skin or GI domains of the ISM-SAF at baseline. 4. In Part 2, patients with an average TSS of at least 14 days ≥ 28 and < 28 during the response period may be enrolled. 5. In Part M, patients must have mMCAS, confirmed by central pathology review of the BM biopsy. An archival biopsy may be used if completed within the last 12 months. 6. In the PK part, patients with an average TSS of < 28 over 14 days may be included if they have a single-domain score of at least 7. 7. In Part S, patients must have SSM, confirmed by central pathology review of the BM biopsy and central review of B and C findings according to the WHO 2022 diagnostic criteria. (BASEC)
Ausschlusskriterien
1. The patient has been diagnosed with one of the following WHO SM sub-classifications: a) Cutaneous mastocytosis only (i.e., without documentation of systemic involvement) b) Systemic mastocytosis with an associated hematological neoplasm of the non-MC lineage (SMAHN) c) Aggressive systemic mastocytosis (ASM) d) Mast cell leukemia (MCL). e) MC sarcoma 2. The patient has been diagnosed with another myeloproliferative disorder (e.g., myelodysplastic syndrome, myeloproliferative neoplasm). 3. The patient has one of the following C findings related to SM of organ damage: a) Cytopenia: i. Absolute neutrophil count < 1.5 × 10^9/l ii. Hemoglobin < 10 g/dl iii. Platelet count < 100,000/µl b) Hepatomegaly with ascites and impaired liver function c) Palpable splenomegaly with hypersplenism d) Malabsorption with hypoalbuminemia and significant weight loss. e) Skeletal lesions: large osteolytic lesions with pathological fractures. f) Life-threatening organ damage in other organ systems caused by MC infiltration into tissues 4. The patient has a Fridericia-corrected QT interval (QTcF) > 470 msec (for females) or > 450 msec (for males). (BASEC)
Studienstandort
Basel, Luzern
(BASEC)
Sponsor
Blueprint Medicines Corporation 45 Sydney Street MA 02139 Cambridge PPD Switzerland GmbH c/o Dufour Treuhand AG Tiergartenrain 3 4054 Basel
(BASEC)
Kontakt für weitere Auskünfte zur Studie
Kontaktperson Schweiz
Dr. med. Axel Rüfer
+41 205 53 30
axel.ruefer@clutterluks.chLuzerner Kantonsspital, Abteilung Hämatologie, Spitalstrasse, 6000 Luzern 16
(BASEC)
Name der bewilligenden Ethikkommission (bei multizentrischen Studien nur die Leitkommission)
Ethikkommission Nordwest- und Zentralschweiz EKNZ
(BASEC)
Datum der Bewilligung durch die Ethikkommission
30.11.2021
(BASEC)
ICTRP Studien-ID
NCT04910685 (ICTRP)
Offizieller Titel (Genehmigt von der Ethikkommission)
Eine randomisierte, doppelblinde, placebokontrollierte Studie der Phase II/III zu BLU-263 bei indolenter systemischer Mastozytose (Prüfplan-Nr. BLU-263-1201) (BASEC)
Wissenschaftlicher Titel
A Randomized, Double-Blind, Placebo-Controlled Phase 2/3 Study of BLU-263 in Indolent Systemic Mastocytosis (ICTRP)
Öffentlicher Titel
(HARBOR) Study to Evaluate Efficacy and Safety of BLU-263 Versus Placebo in Patients With Indolent Systemic Mastocytosis (ICTRP)
Untersuchte Krankheit(en)
Indolent Systemic MastocytosisSmoldering Systemic Mastocytosis (ICTRP)
Untersuchte Intervention
Drug: ElenestinibDrug: Placebo (ICTRP)
Studientyp
Interventional (ICTRP)
Studiendesign
Allocation: Randomized. Intervention model: Parallel Assignment. Primary purpose: Treatment. Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor). (ICTRP)
Ein-/Ausschlusskriterien
Key Inclusion Criteria:
All Participants:
-Participant must have an Eastern Cooperative Oncology Group Performance Status (ECOG PS)
of 0 to 2.
Part 1 and PK groups:
- Participant has confirmed diagnosis of ISM, confirmed by Central Pathology Review
- Participant must have failed to achieve adequate symptom control for 1 or more
Baseline symptoms, as determined by the Investigator, with at least 2 of the
following symptom-directed therapies administered: H1 blockers, H2 blockers,
proton-pump inhibitors, leukotriene inhibitors, cromolyn sodium, corticosteroids, or
omalizumab.
- Participants must have SDT for ISM symptom management stabilized for at least 14
days prior to starting screening procedures.
- For participants receiving corticosteroids, the dose must be = 20 mg/day prednisone
or equivalent, and the dose must be stable for = 14 days.
Part K:
-Participant has confirmed diagnosis of ISM, confirmed by Central Pathology Review
Part S:
-Participant has confirmed diagnosis of SSM, confirmed by Central Pathology Review of BM
biopsy and central review of B- and C-findings by WHO diagnostic criteria.
Part 2:
-Participant has confirmed diagnosis of ISM, confirmed by Central Pathology Review
Key Exclusion Criteria:
- Participant has been diagnosed with any of the following WHO systemic mastocytosis
(SM) sub-classifications: cutaneous mastocytosis only, SM with an associated
hematologic neoplasm of non-MC lineage (SM-AHN), aggressive SM, mast cell leukemia,
or mast cell sarcoma.
- Participant has been diagnosed with another myeloproliferative disorder.
- Participant has organ damage attributable to SM.
- Participant has clinically significant, uncontrolled, cardiovascular disease
- Participant has a QT interval corrected using Fridericia's formula (QTcF) > > 470
milliseconds (msec) (for females) or > 450 msec (for males).
- Participant has a history of a primary malignancy that has been diagnosed or
required therapy within 3 years. The following prior malignancies are not
exclusionary: completely resected basal cell and squamous cell skin cancer,
curatively treated localized prostate cancer, and completely resected carcinoma in
situ of any site.
- Time since any cytoreductive therapy including masitinib and midostaurin should be
at least 5 half-lives or 14 days (whichever is longer), and for cladribine,
interferon alpha, pegylated interferon, or antibody therapy < 28 days or 5
half-lives of the drug (whichever is longer), before beginning the screening period.
- Participant has received radiotherapy or psoralen and ultraviolet A (PUVA) therapy <
14 days before beginning the screening period.
Other protocol-defined criteria apply. (ICTRP)
nicht verfügbar
Primäre und sekundäre Endpunkte
Part 3: Number of participants with Adverse Events (AEs);Part 3: Change from baseline in ISM-SAF TSS;Part 1: Number of participants with Treatment-emergent Adverse Events (TEAEs);Part 1: Mean change from baseline in ISM-Symptom in Assessment Form (ISM-SAF) Total Symptom Score (TSS);Part 2: Mean change from baseline in ISM-SAF TSS (ICTRP)
Part 1: Change from baseline in serum tryptase;Part 1: Change from baseline in KIT D816V allele fraction in blood;Part 1: Change from baseline in Bone Marrow (BM) mast cells;Part 1: Mean change from baseline in ISM-SAF individual symptom scores;Part 1: Time to achieve 30% reduction from baseline in ISM-SAF TSS;Part 1: Time to achieve 30% reduction from baseline in ISM-SAF domain scores;Part 2: Proportion of participants achieving normalized tryptase;Part 2: Proportion of participants who achieve an undetectable level or at least a 50% reduction in KIT D816V Variant Allele Frequency (VAF);Part 2: Proportion of participants achieving symptom control as defined by achieving mild symptoms;Part 2: Mean percent change from baseline in Bone Mineral Density (BMD);Part 2: Mean change from baseline in the annualized rate of anaphylaxis events;Part 2: Mean change from baseline in Quality of Life (QoL) scores;Part 2: Mean change from baseline in ISM-SAF domain scores;Part 2: Number of participants with AEs;Part 2: Proportion of participants with a 50% reduction in ISM-SAF TSS;Part 2: Proportion of participants with a 50% reduction in ISM-SAF domain scores;Part 2: Proportion of participants with a 30% reduction in ISM-SAF TSS;Part 2: Proportion of participants with a 30% reduction in ISM-SAF domain scores;Part 3: Proportion of participants achieving symptom control as defined by achieving mild symptoms;Part 3: Change from baseline in ISM-SAF domain scores;Part 3: Proportion of participants achieving a normalized tryptase;Part 3: Change from baseline in BMD;Part 3: Change from baseline in the annualized rate of anaphylaxis events;Parts 2 and 3: Change from baseline in serum tryptase;Parts 2 and 3: Change from baseline in KIT D816V allele fraction in blood;Parts 2 and 3: Change from baseline in Bone Marrow (BM) mast cells;Parts 2 and 3: Proportion of participants achieving controlled disease;Parts 2 and 3: Change from baseline in skin lesions as assessed by the fractional body surface area of the most affected skin area;Parts 2 and 3: Change from baseline in the number of concomitant medications identified as SDT;Parts 2 and 3: Change from baseline in ISM-SAF Individual Symptom Scores;Parts 2 and 3: Change from baseline in ISM-SAF Lead (most severe) Symptom Score;Parts 2 and 3: Change from baseline in QoL scores;Part S: Number of participants with AEs;Part S: Proportion of participants who achieve a Pure Pathologic Response (PPR);Part S: Mean change from baseline in ISM-SAF;Part K: Number of participants with AEs;Part K: Change from baseline in serum tryptase;Part K: Change from baseline in KIT D816V allele fraction in blood;Part K: Mean change from baseline in ISM-SAF TSS;Part K: Change from baseline in QoL scores (ICTRP)
Registrierungsdatum
nicht verfügbar
Einschluss des ersten Teilnehmers
nicht verfügbar
Sekundäre Sponsoren
nicht verfügbar
Weitere Kontakte
Blueprint Medicines, medinfo@blueprintmedicines.com, 617-714-6707 (ICTRP)
Sekundäre IDs
BLU-263-1201 (ICTRP)
Angaben zur Verfügbarkeit von individuellen Teilnehmerdaten
nicht verfügbar
Weitere Informationen zur Studie
https://clinicaltrials.gov/ct2/show/NCT04910685 (ICTRP)
Ergebnisse der Studie
Zusammenfassung der Ergebnisse
nicht verfügbar
Link zu den Ergebnissen im Primärregister
nicht verfügbar