Phase 2/3 Randomized, Double-Blind, Placebo-Controlled Study of Elenestinib in Patients with Indolent Systemic Mastocytosis and Smoldering Systemic Mastocytosis
- Trial ID
- 2024-516728-32-00
- Protocol
- BLU-263-1201
- Sponsor
- Blueprint Medicines Corp.
Trial statistics
Diseases & Conditions
Objectives
The primary objective of this study is to determine the recommended dose (**RD**) of **elenestinib** in patients with **Indolent Systemic Mastocytosis** (ISM) and Smoldering Systemic Mastocytosis (SSM). Establishing the RD is clinically significant as it ensures the optimal balance between efficacy and safety, which is crucial for the effective management of these conditions.
Secondary objectives include:
- Assessing changes in measures of mast cell burden and individual symptom scores using the ISM-SAF (Indolent Systemic Mastocytosis Symptom Assessment Form) from treatment with elenestinib plus best supportive care (BSC) or placebo plus BSC.
- Evaluating the time to achieve a 30% reduction in ISM-SAF Total Symptom Score (TSS), Gastrointestinal Symptom Score (GSS), Skin Symptom Score (SSS), and Neurocognitive Symptom Cluster Score.
- Determining if treatment with elenestinib plus BSC improves outcomes compared to placebo plus BSC, as assessed using serum tryptase levels, PB KIT D816V allele fraction, mean change in ISM-SAF TSS from baseline, and bone marrow mast cells.
- Assessing the long-term safety, tolerability, and efficacy of treatment with elenestinib.
- Evaluating changes in BSC usage for systemic mastocytosis symptoms, other patient-reported outcomes (PROs), and quality of life (QoL) measures.
- Assessing the safety and tolerability of elenestinib in patients with SSM, response in mast cell measures via PPR criteria, changes in disease-related symptom burden, and the pharmacokinetics (PK) of elenestinib.
Participants
The clinical trial involves a total of **74 participants** diagnosed with **Indolent Systemic Mastocytosis** and Smoldering Systemic Mastocytosis (SSM). The study population includes both male and female subjects, aged 16 years and older, with specific age restrictions in certain countries such as France, Sweden, Germany, and Spain, where participants must be at least 18 years old. Participants were selected based on the presence of KIT D816V mutation in peripheral blood or bone marrow, or CD25+ mast cells in bone marrow, along with symptoms consistent with mast cell activation affecting at least two organ systems. The trial includes individuals with an Eastern Cooperative Oncology Group Performance Status (ECOG PS) of 0 to 2, indicating a general good health status. Lifestyle considerations such as diet or physical activity are not specified, but participants must have stabilized best supportive care for symptom management prior to screening. The trial also includes vulnerable populations, ensuring a comprehensive assessment of the investigational treatment's efficacy and safety across diverse patient groups.
Plans and Procedures
The clinical trial is designed as a **randomized, double-blind, placebo-controlled** study to evaluate the efficacy and safety of **ELENESTINIB** in patients with **Indolent Systemic Mastocytosis**. The trial is structured in multiple phases, with the primary objective being to determine the recommended dose of ELENESTINIB. The study will involve the administration of ELENESTINIB in the form of film-coated tablets, with a maximum daily dose of 100 mg and a total treatment period of up to 208 days. The trial is expected to commence recruitment in April 2025 and conclude by December 2027.
Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to assess eligibility based on criteria such as age, presence of KIT D816V mutation, and symptom severity. Following successful screening, participants will be randomized to receive either ELENESTINIB or placebo. The trial includes several follow-up visits to monitor safety and efficacy, with primary endpoints focusing on safety, tolerability, and changes in symptom scores. Secondary endpoints will assess changes in serum tryptase levels and KIT D816V allele fraction.
The expected duration of participant involvement is approximately 208 days, with conditions for early termination including adverse events, withdrawal of consent, or failure to adhere to protocol requirements. The end-of-study visit will evaluate the overall outcomes and gather final safety data. The trial aims to provide comprehensive data on the therapeutic potential of ELENESTINIB in managing symptoms of Indolent Systemic Mastocytosis.
Treatment
The clinical trial involves the administration of **ELENESTINIB**, a film-coated tablet formulated with the active substance **elenestinib phosphate**. This investigational medication is provided by Blueprint Medicines and is classified as a chemical substance. The pharmaceutical form is a film-coated tablet, designed for **oral use**. The maximum daily dose is 100 mg, with a total maximum dose of 146,000 mg over a treatment period of up to 208 days. The trial aims to determine the recommended dose (RD) of elenestinib in participants with indolent systemic mastocytosis. Participant compliance with the dosing schedule will be monitored throughout the study.
In addition to the experimental treatment, the study includes the use of **placebo tablets**. These tablets are administered in a manner identical to the experimental medication to maintain the double-blind nature of the trial. The placebo serves as a comparator to evaluate the efficacy and safety of elenestinib. The placebo tablets are also administered orally, ensuring consistency in the route of administration across all study arms. Compliance with the placebo regimen will be monitored similarly to the active treatment group.
Efficacy
The efficacy of the investigational product, **elenestinib**, in the treatment of indolent systemic mastocytosis will be assessed using several primary and secondary endpoints. The primary efficacy endpoints include the mean change in the Indolent Systemic Mastocytosis Symptom Assessment Form Total Symptom Score (ISM-SAF TSS) from baseline at Week 13, and the proportion of patients with moderate to severe indolent systemic mastocytosis (ISM) who achieve at least a 30% reduction in ISM-SAF TSS from baseline at Week 25. Additionally, safety and tolerability will be evaluated through adverse events (AEs), serious adverse events (SAEs), and changes in safety laboratory parameters, vital signs, and ECG evaluations.
Secondary efficacy endpoints will measure the mean change in serum tryptase levels, KIT D816V allele fraction in blood, and bone marrow mast cells from baseline at Week 13. The study will also assess the mean change in ISM-SAF individual symptom scores from baseline at 12 weeks of treatment, and the time to achieve a 30% reduction in ISM-SAF TSS, ISM-SAF Global Symptom Score (GSS), ISM-SAF Symptom Severity Score (SSS), and ISM-SAF Neurocognitive Symptom Cluster Score from randomization among patients who achieve such a reduction on or before 12 weeks of treatment. Furthermore, the proportion of patients achieving at least a 50% reduction in serum tryptase and KIT D816V allele fraction from baseline to after 24 weeks of treatment will be evaluated.
Inclusion and Exclusion Criteria
Inclusion Criteria
- All patients. 1. Patient must be ≥ 18 years of age at the time of signing the informed consent/assent.
- Treatment with a prior approved selective KIT inhibitor for ISM.
- Patient must have failed to achieve adequate symptom control for 1 or more Baseline symptoms as determined by the Investigator’s best clinical judgment, 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.
- Patient must have moderate to severe symptoms during the eligibility period.
- If the patient is receiving corticosteroids, the dose must be ≤ 20 mg/day prednisone or equivalent, and the dose must be stable for ≥ 14 days before beginning the 14-day eligibility Screening Period for assessment of ISM-SAF.
- If on a bone-targeted therapy other than calcium and vitamin D, including hormone replacement therapy, patients must be on a stable dose for least 24 weeks prior to first treatment day unless the administration frequency of the drug is less frequent than once every 24 weeks for which at least 2 consecutive doses must have been administrated to the patient following the schedule.
- Accrual may be limited to patients who have specific disease manifestations (ie, GI involvement) to better explore the impact of these features on PK.
- The patient’s ISM symptom-directed therapies (e.g., H1 and H2 blockers) must be stable (same dose, no new medications ≥ 14 days before beginning the 14-day eligibility Screening Period for the assessment of ISM-SAF).
- Patients with SSM in Part S: 11.Patient 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 . No archival BM biopsies will be accepted without approval from the Sponsor.
- Patients in Part K Previously Treated With Approved Selective KIT Inhibitors: 12. Patient has a centrally confirmed diagnosis of ISM. In consultation with the Sponsor, archival biopsy may be used if completed within the past 12 months and there is no evidence of progressive disease.
- Patients with 14-day average TSS obtained no earlier than 15 days after the discontinuation of the prior approved selective KIT inhibitor may be enrolled.
- Patients with ISM in Part 1, 2 and PK groups. 4. Patient has confirmed diagnosis of ISM, confirmed by Central Pathology Review of BM biopsy and central review of B- and C-findings by WHO diagnostic criteria. Archival biopsy may be used if completed within the past 12 months.
- Patient must have an Eastern Cooperative Oncology Group Performance Status (ECOG PS) of 0 to 2. With ISM in Part 1 and Part 2
- Patients with ISM in Part 1. 3. Patient must have moderate-to-severe symptoms based on minimum mean total symptom score (TSS) of the ISM Symptom Assessment Form (ISM-SAF) over the 14-day eligibility screening period. With ISM in Part 1, Part 2 and PK groups
- Patient must have failed to achieve adequate symptom control for 1 or more Baseline symptoms, as determined by the Investigators best clinical judgment, 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.
- Patients must have SDT for ISM symptom management stabilized without any new or worsening of symptoms and/or AEs for at least 14 days prior to starting 14-day ISM-SAF TSS eligibility period (Part 1 only).
- Patients in Part 2: 17. Patient has a centrally confirmed diagnosis of ISM. Archival biopsy may be used if completed within the past 12 months.
- For patients receiving corticosteroids, the dose must be ≤ 20 mg/d prednisone or equivalent, and the dose must be stable for ≥ 14 days before beginning the 14-day eligibility Screening Period for assessment of ISM-SAF for Part 1 or PK.
- The patient’s ISM symptom-directed therapies (eg, H1 and H2 blockers) must be stable (same dose, no new medications ≥ 14 days before beginning the 14-day eligibility Screening Period for the assessment of ISM-SAF).
- Patients must have a washout period of their prior approved selective KIT inhibitor for ISM of at least 28 days prior to the first elenestinib dose.
Exclusion Criteria
- Patient has been diagnosed with any of the following WHO SM sub-classifications: cutaneous mastocytosis only, SM-AHN, ASM, MCL, Mast cell sarcoma.
- Patient has been diagnosed with another myeloproliferative disorder.
- Patient has organ damage attributable to SM.
- Patient has a QT interval corrected using Fridericia's formula (QTcF) > 470 msec (for females) or > 450 msec (for males).
- Patient has clinically significant, uncontrolled, cardiovascular disease.
- Patient 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 mastinib 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 assessments. For omalizumab, washout is not necessary, and patients can continue on omalizumab therapy.
- Patient has received radiotherapy or PUVA therapy < 14 days before beginning the screening assessments.
Trial Status by Country
| Country | Status | Start of Recruitment | Planned Patients |
|---|---|---|---|
 Austria | Recruiting | 06 Jan 2022 | 6 |
 Belgium | Recruiting | 06 Jan 2022 | 16 |
 Czechia | Recruiting | 06 Jan 2022 | 10 |
 Denmark | Recruiting | 06 Jan 2022 | 7 |
 France | Recruiting | 06 Jan 2022 | 127 |
 Germany | Recruiting | 06 Jan 2022 | 54 |
 Greece | Recruiting | 06 Jan 2022 | 10 |
 Ireland | Recruiting | 06 Jan 2022 | 2 |
 Italy | Recruiting | 06 Jan 2022 | 29 |
 The Netherlands | Recruiting | 06 Jan 2022 | — |
Sites & Investigators
Investigational Products
Details about the medicinal products being studied in this clinical trial.
| Product Name | Role in Trial | Formulation | Administration | Max Daily Dose | Treatment Duration | EU MP Number |
|---|---|---|---|---|---|---|
ELENESTINIB | Test | FILM-COATED TABLET | ORAL USE | 100 | 260 | PRD12079972 |
Placebo tablets | Placebo | N/A | — | — | — | N/A |
ELENESTINIB | Test | FILM-COATED TABLET | ORAL USE | 100 | 260 | PRD8837820 |
ELENESTINIB | Test | FILM-COATED TABLET | ORAL USE | 100 | 260 | PRD12079973 |
ELENESTINIB | Test | FILM-COATED TABLET | ORAL USE | 100 | 260 | PRD8837819 |