| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Indolent Systemic Mastocytosis (ISM) and monoclonal Mast Cell Activation Syndrome (mMCAS) |
|
| E.1.1.1 | Medical condition in easily understood language |
| A Study of BLU-263 in patients with Indolent Systemic Mastocytosis |
|
| E.1.1.2 | Therapeutic area | Diseases [C] - Blood and lymphatic diseases [C15] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 27.0 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10056452 |
| E.1.2 | Term | Indolent systemic mastocytosis |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
|
| E.1.3 | Condition being studied is a rare disease | Yes |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
Part 1: To determine RD of elenestinib.
Part 2: To assess if treatment with elenestinib+BSC improves outcomes compared to placebo + BSC, as assessed using the ISM-SAF.
Part 3:
- To assess the long-term safety and tolerability of treatment with elenestinib.
- To assess the long-term efficacy of treatment with elenestinib. |
|
| E.2.2 | Secondary objectives of the trial |
Part 1:
To assess the change in measures of mast cell burden from treatment withelenestinib+BSC or placebo+BSC
To assess the change in ISM-SAF individual symptom scores from treatment withelenestinib+BSC or placebo+BSC
To assess the time to achieve a 30% reduction in ISM-SAF TSS, ISM-SAF GSS, ISM-SAF SSS, and ISM-SAF Neurocognitive Symptom Cluster Score
Part 2:
To assess if treatment with elenestinib+BSC improves outcomes compared to placebo+BSC, as assessed using:
- serum tryptase
- PB KIT D816V allele fraction
- mean change in ISM-SAF TSS from Baseline
- BM mast cells
Part 3:
To assess the change in
- measures of mast cell burden
- BSC usage for SM symptoms
- ISM-SAF Individual Symptom Scores and ISM-SAF Lead Symptom Score (LSS)
- in other PROs and QoL measures
To assess the time to achieve a 30% reduction in ISM-SAF TSS, ISM-SAF GSS, ISM-SAF SSS, and ISM-SAF Neurocognitive Symptom Cluster Score |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
All Patients
1. Patient must be ≥ 16 years of age at the time of signing the informed consent/assent. (In France, Sweden, Germany, and Spain, only patients
who are ≥ 18 years of age are allowed).
2. Patient must have an Eastern Cooperative Oncology Group Performance Status (ECOG PS) of 0 to 2.
With ISM in Part 1 and Part 2
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
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.
5. Patient 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 symptomatic therapies administered: H1 blockers, H2 blockers, proton-pump inhibitors, leukotriene inhibitors, cromolyn sodium, corticosteroids, or omalizumab.
6. Patients must have BSC for ISM symptom management stabilized for at least 14 days prior to starting screening procedures.
7. For patients receiving corticosteroids, the dose must be ≤ 20 mg/d prednisone or equivalent, and the dose must be stable for ≥ 14 days.
With mMCAS in Part M
8. Patients must have mMCAS, confirmed by Central Pathology Review of BM biopsy. An archival biopsy may be used if completed within the past
12 months.
9. Patients must have tryptase < 20 ng/mL.
10. Patients must have KIT D816V in PB or BM and/or CD25+ Mast cells in BM.
11. Patients must have symptoms consistent with mast cell activation (despite BSC) in at least two organ systems characterized by cutaneous
flushing, tachycardia, syncope, hypotension, diarrhea, nausea, vomiting and GI cramping and sBT levels above 8 ng/mL OR Severe (Ring and
Messmer grading ≥ II), recurrent anaphylaxis, including but not limited to hymenoptera venom, drug or food, regardless of sBT levels.
With ISM in PK Groups
12. Accrual may be limited to patients who have specific disease manifestations (ie, GI involvement) or are taking acid-reducing agents to better explore the impact of these features on PK.
With SSM in Part S:
13.Patient has confirmed diagnosis of SSM, confirmed by Central Pathology Review of BM biopsy and central review of B- and C-findings by WHO 2022 diagnostic criteria . No archival BM biopsies will be accepted without approval from the Sponsor. |
|
| E.4 | Principal exclusion criteria |
Key Exclusion Criteria:
1. Patient has been diagnosed with any of the following WHO SM subclassifications: cutaneous mastocytosis only, SM-AHN, ASM, MCL, Mast cell sarcoma.
2. Patient has been diagnosed with another myeloproliferative disorder.
3. Patient has organ damage C-findings attributable to SM.
4. Patient has a QT interval corrected using Fridericia's formula (QTcF) > 470 msec (for females) or > 450 msec (for males).
5. Patient has clinically significant, uncontrolled, cardiovascular disease.
6. Patient has previously received treatment with any selective KIT inhibitors (avapritinib, bezuclastinib, and ripretinib).
7. 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.
8. 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 period.
9. Patient has received radiotherapy or PUVA therapy < 14 days before beginning the screening period.
10. Patient has known active SARS-CoV-2infection (Germany Only).
11. Patients not eligible for an MRI due to contraindications (eg, patients with implanted defibrillators or other metallic devices not approved for MRI [Germany only]).
|
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
Part 1
Safety and tolerability as determined by AEs, serious adverse events (SAEs), and changes in safety laboratory parameters, vital signs, and ECG evaluations
PK and PD data
The mean change in ISM-SAF TSS from Baseline at Week 13.
Part 2
Proportion of patients with moderate to severe ISM who achieve at least a 30% reduction in ISM-SAF TSS from Baseline at Week 25
Part 3
Safety and tolerability determined by AEs, SAEs, and changes in safety laboratory parameters, vital signs, and ECG evaluations
The mean change in ISM-SAF TSS from elenestinib Baseline (the last available observation prior to the first dose of elenestinib) |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
Part 1: At Week 13
Part 2: At Week 25
Part 3: Ongoing basis
|
|
| E.5.2 | Secondary end point(s) |
Part 1:
The mean change in the following measures from Baseline at Week 13:
•Serum tryptase
•KIT D816V allele fraction in blood
•BM mast cells
-The mean change in ISM-SAF individual symptom scores from Baseline at 12 weeks of treatment (Week 13)
-The time to achieve a 30% reduction in ISM-SAF TSS, ISM-SAF GSS, ISM-SAF SSS, and ISM-SAF Neurocognitive Symptom Cluster Score from randomization among patients who achieve such a reduction on or before 12 weeks of treatment (Week 13)
Part 2:
- The proportion of patients who achieve at least a 50% reduction in serum tryptase from Baseline to after 24 weeks of treatment (Week 25), among patients with Baseline moderate to severe ISM and Baseline tryptase ≥ 20 ng/mL.
- The proportion of patients who achieve at least a 50% reduction in peripheral blood KIT D816V allele fraction, or a reduction to undetectable levels, from Baseline to after 24 weeks of treatment (Week 25), among patients with Baseline moderate to severe ISM and detectable mutation at Baseline.
- The mean change in ISM-SAF from Baseline to after 24 weeks of treatment (Week 25), among patients with Baseline moderate to severe ISM
- The proportion of patients who achieve at least a 50% reduction in BM mast cells, or a reduction to no aggregates, from Baseline at Week 25, among patients with Baseline moderate to severe ISM and aggregates at Baseline.
Part 3:
-The mean change in the following measures of mast cell burden from BLU-263 Baseline:
•Serum tryptase
•KIT D816V allele fraction in blood
-The change in the number of concomitant medications identified as BSC from Baseline
-The mean change in ISM-SAF Individual Symptom Scores from Baseline
-The mean change in ISM-SAF LSS from Baseline
The time to achieve a 30% reduction in ISM-SAF TSS, ISM-SAF GSS, ISM-SAF SSS, and ISM-SAF Neurocognitive Symptom Cluster Score from the first dose of elenestinib among patients who achieve such a reduction on or before 1 year of elenestinib therapy
The mean change in the following measures from Baseline at Week 25:
•MC-QoL score
•PGI-S score
•SF-12 score
•EQ-5D-5L score
|
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
Part 1 - baseline to week 13;
Part 2 - baseline to week 25;
Part 3 - ongoing basis |
|
| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | Yes |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | Yes |
| E.6.7 | Pharmacodynamic | Yes |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | Yes |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | Yes |
| E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | Yes |
| E.8.1.1 | Randomised | Yes |
| E.8.1.2 | Open | No |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | Yes |
| E.8.1.5 | Parallel group | No |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | No |
| E.8.2.2 | Placebo | Yes |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 4 |
| E.8.3 |
The trial involves single site in the Member State concerned
| Yes |
| E.8.4 | The trial involves multiple sites in the Member State concerned | No |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 1 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 42 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
| Switzerland |
| Australia |
| United Kingdom |
| United States |
| Austria |
| Belgium |
| Denmark |
| France |
| Germany |
| Italy |
| Netherlands |
| Norway |
| Portugal |
| Spain |
| Sweden |
|
| E.8.7 | Trial has a data monitoring committee | Yes |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
|
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 7 |
| E.8.9.1 | In the Member State concerned months | 0 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 7 |
| E.8.9.2 | In all countries concerned by the trial months | 0 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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