HARBOR: Study of BLU-263 for Indolent Systemic Mastocytosis

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] - Neoplasms [C04], Diseases [C] - Immune System Diseases [C20]

Trial duration

29 Oct 2021 → ongoing

Decision date (initial)

2024-11-12

Transition trial

Yes

Low-intervention

No

Rare-disease indication

Yes

Vulnerable population

Yes

Funding sources

Blueprint Medicines Corporation

External identifiers

EU CT number

2024-516728-32-00

EudraCT number

2020-005173-28

ClinicalTrials.gov

NCT04910685

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

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

(Part 1) To determine the recommended dose(s) of elenestinib
(Part 2) To assess if treatment with elenestinib + SDT reduces total symptom score (TSS) compared to placebo + SDT,
as assessed using the ISM-SAF
(Part 3)
- To assess the safety and tolerability of treatment with elenestinib.
- To assess the efficacy of treatment with elenestinib.

Secondary objectives 6

1. Part 1: 1. To assess the change in measures of mast cell burden from treatment with elenestinib+ SDT or placebo+ SDT 2. To assess the change in ISM-SAF individual symptom scores from treatment with elenestinib+ SDT or placebo+ SDT 3. To assess the time to achieve a 30% reduction in ISM-SAF TSS, ISM-SAF GSS, ISM-SAF SSS, and ISM-SAF
2. Part 2: To assess if treatment with elenestinib+ SDT - reduces tryptase compared to placebo+ SDT, as assessed using: serum tryptase - reduces KIT D816V VAF levels compared to placebo + SDT, as assessed using PB KIT D816V allele fraction - achieves symptom control compared to placebo + SDT, as assessed by patients achieving symptom control defined by mild or absent symptoms in patients with moderate/severe symptoms - improves BMD outcomes compared to placebo + SDT, as assessed by changes in BMD - decreases the frequency of anaphylaxis compared to placebo + SDT, as assessed by anaphylaxis events - improves QoL compared to placebo + SDT
3. Part 3: To assess the change in disease symptom control, ISM-SAF domain scores, BMD, and anaphylaxis rates. To determine if treatment with elenestinib + BSC normalizes tryptase
4. Part 2 and Part 3 Shared: 1. To assess the change in measures of mast cell burden 2. To assess disease control 3. To assess change in SM-related skin lesions 4. To assess the change in SDT usage for SM symptoms 5. To assess the change in ISM-SAF Individual Symptom Scores 6. To assess the change in ISM-SAF Lead (most severe) Symptom Score 7. To assess changes in other PROs and QoL measures
5. Part K 1. To assess the safety and tolerability of elenestinib in patients with ISM 2. To assess the change in measures of mast cell burden 3. To assess the efficacy of treatment with elenestinib 4. To assess changes in other PROs and QoL measures
6. Part S: 1. To assess the safety and tolerability of elenestinib in patients with SSM. 2. To assess response in mast cell measures via PPR criteria. 3. To assess changes in disease-related symptom burden. 4. To assess the PK of elenestinib

Conditions and MedDRA coding

Indolent Systemic Mastocytosis and SSM

Study design 7 periods

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 20

1. All patients. 1. Patient must be ≥ 18 years of age at the time of signing the informed consent/assent.
2. 15. Treatment with a prior approved selective KIT inhibitor for ISM.
3. 19. 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.
4. 18. Patient must have moderate to severe symptoms during the eligibility period.
5. 21. 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.
6. 22. 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.
7. 10. Accrual may be limited to patients who have specific disease manifestations (ie, GI involvement) to better explore the impact of these features on PK.
8. 20. 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).
9. 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.
10. 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.
11. 13. 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.
12. 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.
13. 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
14. 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
15. 5. 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.
16. 6. 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).
17. 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.
18. 7. 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.
19. 8. 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).
20. 14. 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 8

1. Patient has been diagnosed with any of the following WHO SM sub-classifications: cutaneous mastocytosis only, SM-AHN, ASM, MCL, Mast cell sarcoma.
2. Patient has been diagnosed with another myeloproliferative disorder.
3. Patient has organ damage 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 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.
7. 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.
8. Patient has received radiotherapy or PUVA therapy < 14 days before beginning the screening assessments.

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 3

1. Part 1: Safety and tolerability as determined by adverse events, serious treatment-emergent adverse events, 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.
2. Part 2: Mean change in ISM-SAF TSS from Baseline to after 48 weeks of treatment (Week 49), as compared to placebo
3. Part 3: 1. Safety and tolerability determined by AEs, SAEs, and changes in safety laboratory parameters, vital signs, and ECG evaluations. 2. Change in ISM-SAF TSS from elenestinib Baseline (T the last available observation prior to the first dose of elenestinib)

Secondary endpoints 10

1. 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)."
2. Part 2: 1. Proportion of patients achieving a normalized tryptase after 48weeks of treatment (Week 49) as compared to placebo
3. Part 2: 4. Mean percent change in lumbar BMD from Baseline to after 48 weeks of treatment (Week 49), compared to placebo among patients with baseline osteopenia or osteoporosis
4. Part 2: 5. Mean change in the annualized rate of anaphylaxis events between the Screening Period and Weeks 25 to 48 of treatment compared to placebo.
5. Part 2: 6. Mean change in QoL score from Baseline to after 48 weeks of treatment (week 49) as compared to placebo.
6. Part 3: 1. Proportion of patients achieving symptom control as defined by achieving mild symptoms 2. Change in ISM-SAF domain scores including the ISM-SAF GSS, ISM-SAF SSS, and ISM-SAF NSS 3. Change in BMD 4. Proportion of patients achieving a normalized tryptase 5. Change in the annualized rate of anaphylaxis events
7. Part 2 and Part 3 Shared: 1. Change in the following measures: Serum tryptase; KIT D816V allele fraction in blood, and BM mast cells. 2. Proportion of patients achieving controlled disease 3. Change in skin lesions as assessed by the fractional body surface area of the most affected skin area 4. Change in the number of concomitant medications identified as SDT 5. Change in ISM-SAF Individual Symptom Scores 6. Change in ISM-SAF Lead (most severe) Symptom Score
8. Part 2 and Part 3 Shared (translations continued)
9. Part 2: 2. Proportion of patients achieving an undetectable level or ≥ 50% reduction in KIT D816V-VAF Baseline to after 48 weeks of treatment (Week 49) as compared to placebo among patients with detectable mutation at Baseline
10. Part 2: 3. Proportion of patients symptom control as defined by achieving mild symptoms after 48 weeks of treatment as compared to placebo.

Investigational products

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

Test 4

Placebo 1

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 22

Locations

15 EU/EEA countries · 51 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

Documents 112 files

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

Application history

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