Trial Review

Registering a new trial?

To achieve prospective registration, we recommend submitting your trial for registration at the same time as ethics submission.

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been endorsed by the ANZCTR. Before participating in a study, talk to your health care provider and refer to this information for consumers
Trial details imported from ClinicalTrials.gov

For full trial details, please see the original record at https://clinicaltrials.gov/study/NCT04910685




Registration number
NCT04910685
Ethics application status
Date submitted
17/05/2021
Date registered
2/06/2021
Date last updated
12/11/2024

Titles & IDs
Public title
(HARBOR) Study to Evaluate Efficacy and Safety of BLU-263 Versus Placebo in Patients With Indolent Systemic Mastocytosis
Scientific title
A Randomized, Double-Blind, Placebo-Controlled Phase 2/3 Study of BLU-263 in Indolent Systemic Mastocytosis
Secondary ID [1] 0 0
BLU-263-1201
Universal Trial Number (UTN)
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Indolent Systemic Mastocytosis 0 0
Monoclonal Mast Cell Activation Syndrome 0 0
Smoldering Systemic Mastocytosis 0 0
Condition category
Condition code
Skin 0 0 0 0
Other skin conditions
Blood 0 0 0 0
Other blood disorders
Inflammatory and Immune System 0 0 0 0
Other inflammatory or immune system disorders

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Treatment: Drugs - Elenestinib
Treatment: Drugs - Placebo

Experimental: (Part 1) Elenestinib Dose 1 + BSC - Patients will receive best supportive care (BSC) and Dose 1 of elenestinib. BSC will be determined on a per patient basis. Elenestinib will be administered orally, once daily until completion of Part 1.

Experimental: (Part 1) Elenestinib Dose 2 + BSC - Patients will receive BSC and Dose 2 of elenestinib. BSC will be determined on a per patient basis. Elenestinib will be administered orally, once daily until completion of Part 1.

Experimental: (Part 1) Elenestinib Dose 3 + BSC - Patients will receive BSC and Dose 3 of elenestinib. BSC will be determined on a per patient basis. Elenestinib will be administered orally, once daily until completion of Part 1.

Placebo comparator: (Part 1) Placebo + BSC - Patients will receive BSC and matching placebo. BSC will be determined on a per patient basis. Placebo will be administered orally, once daily until completion of Part 1

Experimental: (Part 2) Elenestinib RD + BSC - Patients will receive BSC and the recommended dose (RD) of elenestinib. BSC will be determined on a per patient basis. Elenestinib will be administered orally, once daily for approximately 24 weeks

Placebo comparator: (Part 2) Placebo + BSC - Patients will receive BSC and matching placebo. BSC will be determined on a per patient basis. Placebo will be administered orally, once daily once daily for approximately 24 weeks

Experimental: (Part 3) Elenestinib RD + BSC - Patients will receive open-label BSC and the RD of elenestinib for up to approximately 4 years.

Experimental: (Part M) Elenestinib RD + BSC - Patients will receive BSC and the RD of elenestinib. BSC will be determined on a per patient basis. Elenestinib will be administered orally, once daily for the duration of participation in the study.

Experimental: PK Groups (Dose 2 or Dose 3) - Patients will receive BSC and Dose 2 or Dose 3 of elenestinib. BSC will be determined on a per patient basis. Elenestinib will be administered orally for the duration of participation in the study.

Experimental: (Part S) Elenestinib + BSC - Participants with Smoldering Systemic Mastocytosis (SSM) will receive open-label BSC and elenestinib for up to approximately 4 years.


Treatment: Drugs: Elenestinib
Elenestinib oral tablet

Treatment: Drugs: Placebo
Placebo oral tablet
Intervention code [1] 0 0
Treatment: Drugs
Comparator / control treatment
Control group

Outcomes
Primary outcome [1] 0 0
Parts 1 and 3: Number of participants with Adverse Events (AEs)
Timepoint [1] 0 0
Up to 4 years
Primary outcome [2] 0 0
Part 2: Objective Response Rate (ORR), defined as proportion of patients who achieve =30% reduction from baseline in ISM-Symptom in Assessment Form (ISM-SAF) Total Symptom Score (TSS)
Timepoint [2] 0 0
Baseline, Week 25
Primary outcome [3] 0 0
Parts 1 and 3: Mean change from baseline in ISM-SAF TSS
Timepoint [3] 0 0
Baseline up to 4 years
Secondary outcome [1] 0 0
Parts 1, 2, and 3: Mean change from baseline in measures of mast cell burden
Timepoint [1] 0 0
Baseline up to 4 years
Secondary outcome [2] 0 0
Parts 1, 2, and 3: Mean change from baseline in ISM-SAF individual symptom scores
Timepoint [2] 0 0
Baseline up to 4 years
Secondary outcome [3] 0 0
Parts 1, 2, and 3: Time to achieve 30% reduction from baseline in ISM-SAF scores
Timepoint [3] 0 0
Baseline up to 4 years
Secondary outcome [4] 0 0
Part 2: Proportion of patients with a =50% reduction from baseline in serum tryptase
Timepoint [4] 0 0
Baseline, Week 25
Secondary outcome [5] 0 0
Part 2: Proportion of patients who achieve at least a 50% reduction in peripheral blood KIT D816V allele fraction, or a reduction to undetectable levels
Timepoint [5] 0 0
Baseline, Week 25
Secondary outcome [6] 0 0
Part 2: Mean change from baseline in ISM-SAF
Timepoint [6] 0 0
Baseline, Week 25
Secondary outcome [7] 0 0
Part 2: Proportion of patients with a =50% reduction in bone marrow mast cells or reduction to no aggregates for patients with aggregates at Baseline
Timepoint [7] 0 0
Baseline, Week 25
Secondary outcome [8] 0 0
Part 2: ORR
Timepoint [8] 0 0
Week 25
Secondary outcome [9] 0 0
Parts 2 and 3: Change form baseline in number of concomitant BSC medications
Timepoint [9] 0 0
Baseline up to 4 years
Secondary outcome [10] 0 0
Parts 2 and 3: Change from baseline in ISM-SAF leading symptom score
Timepoint [10] 0 0
Baseline up to 4 years
Secondary outcome [11] 0 0
Parts 2 and 3: Mean change from baseline in Quality of Life scores
Timepoint [11] 0 0
Baseline up to 4 years
Secondary outcome [12] 0 0
Part 2: Number of participants with AEs
Timepoint [12] 0 0
Up to Week 25
Secondary outcome [13] 0 0
Part S: Number of participants with AEs
Timepoint [13] 0 0
Baseline up to 4 years
Secondary outcome [14] 0 0
Part S: Proportion of participants who achieve a Complete Remission (CR)/Complete remission with partial recovery of peripheral blood counts (CRh), molecular CR/molecular CRh, or Partial Response (PR) based on Pure Pathologic Response (PPR) from Baseline
Timepoint [14] 0 0
Baseline up to 4 years
Secondary outcome [15] 0 0
Part S: Mean change in ISM-SAF from Baseline to after 24 weeks of treatment
Timepoint [15] 0 0
Week 25

Eligibility
Key inclusion criteria
Key

All Patients

-1. Patient must have an Eastern Cooperative Oncology Group Performance Status (ECOG PS) of 0 to 2.

Part 1 and Part 2

* 2. 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.
* 3. 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.
* 4. 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.
* 5. Patients must have BSC for ISM symptom management stabilized for at least 14 days prior to starting screening procedures.
* 6. For patients receiving corticosteroids, the dose must be = 20 mg/d prednisone or equivalent, and the dose must be stable for = 14 days.

Part M

* 7. 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.
* 8. Patients must have tryptase < 20 ng/mL.
* 9. Patients must have KIT D816V in peripheral blood (PB) or BM and/or CD25+ Mast cells in BM.
* 10. 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 gastro-intestinal cramping) and serum blood tryptase (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.

PK Groups

* 11. See inclusion criteria for All patients and Part 1/Part 2
* 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.

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.

Key
Minimum age
16 Years
Maximum age
No limit
Sex
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
* 1. Patient 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.
* 2. Patient has been diagnosed with another myeloproliferative disorder.
* 3. Patient has organ damage C-findings attributable to SM.
* 4. Patient has clinically significant, uncontrolled, cardiovascular disease
* 5. Patient has a QT interval corrected using Fridericia's formula (QTcF) > 480 msec.
* 6. Patient has previously received treatment with any targeted KIT inhibitors.
* 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 psoralen and ultraviolet A (PUVA) therapy < 14 days before beginning the screening period.

Study design
Purpose of the study
Treatment
Allocation to intervention
Randomised controlled trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Masking / blinding
Blinded (masking used)
Who is / are masked / blinded?
The people receiving the treatment/s
The people administering the treatment/s
The people assessing the outcomes
The people analysing the results/data
Intervention assignment
Parallel
Other design features
Phase
Phase 2
Type of endpoint/s
Statistical methods / analysis

Recruitment
Recruitment status
Recruiting
Data analysis
Reason for early stopping/withdrawal
Other reasons
Date of first participant enrolment
Anticipated
Actual
30/11/2021
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
30/06/2028
Actual
Sample size
Target
463
Accrual to date
Final
Recruitment in Australia
Recruitment state(s)
QLD,VIC
Recruitment hospital [1] 0 0
Princess Alexandra Hospital - Woolloongabba
Recruitment hospital [2] 0 0
The Alfred Hospital - Melbourne
Recruitment postcode(s) [1] 0 0
- Woolloongabba
Recruitment postcode(s) [2] 0 0
3004 - Melbourne
Recruitment outside Australia
Country [1] 0 0
United States of America
State/province [1] 0 0
Alabama
Country [2] 0 0
United States of America
State/province [2] 0 0
California
Country [3] 0 0
United States of America
State/province [3] 0 0
Massachusetts
Country [4] 0 0
United States of America
State/province [4] 0 0
Michigan
Country [5] 0 0
United States of America
State/province [5] 0 0
Minnesota
Country [6] 0 0
United States of America
State/province [6] 0 0
New York
Country [7] 0 0
United States of America
State/province [7] 0 0
Ohio
Country [8] 0 0
United States of America
State/province [8] 0 0
Texas
Country [9] 0 0
United States of America
State/province [9] 0 0
Utah
Country [10] 0 0
Austria
State/province [10] 0 0
Linz
Country [11] 0 0
Belgium
State/province [11] 0 0
Antwerpen
Country [12] 0 0
France
State/province [12] 0 0
Amiens
Country [13] 0 0
France
State/province [13] 0 0
Caen
Country [14] 0 0
France
State/province [14] 0 0
Grenoble Cedex 9
Country [15] 0 0
France
State/province [15] 0 0
Limoges Cedex
Country [16] 0 0
France
State/province [16] 0 0
Nantes
Country [17] 0 0
France
State/province [17] 0 0
Paris
Country [18] 0 0
France
State/province [18] 0 0
Poitiers
Country [19] 0 0
France
State/province [19] 0 0
Toulouse
Country [20] 0 0
Germany
State/province [20] 0 0
Aachen
Country [21] 0 0
Germany
State/province [21] 0 0
Berlin
Country [22] 0 0
Germany
State/province [22] 0 0
Erlangen
Country [23] 0 0
Germany
State/province [23] 0 0
Hamburg
Country [24] 0 0
Germany
State/province [24] 0 0
Mannheim
Country [25] 0 0
Germany
State/province [25] 0 0
Munich
Country [26] 0 0
Italy
State/province [26] 0 0
Forli-Cesena
Country [27] 0 0
Italy
State/province [27] 0 0
Lombardia
Country [28] 0 0
Italy
State/province [28] 0 0
Toscana
Country [29] 0 0
Italy
State/province [29] 0 0
Bologna
Country [30] 0 0
Italy
State/province [30] 0 0
Pavia
Country [31] 0 0
Italy
State/province [31] 0 0
Salerno
Country [32] 0 0
Italy
State/province [32] 0 0
Verona
Country [33] 0 0
Netherlands
State/province [33] 0 0
Zuid-Holland
Country [34] 0 0
Netherlands
State/province [34] 0 0
Groningen
Country [35] 0 0
Norway
State/province [35] 0 0
Oslo
Country [36] 0 0
Portugal
State/province [36] 0 0
Lisbon
Country [37] 0 0
Portugal
State/province [37] 0 0
Porto
Country [38] 0 0
Spain
State/province [38] 0 0
Barcelona
Country [39] 0 0
Spain
State/province [39] 0 0
Madrid
Country [40] 0 0
Spain
State/province [40] 0 0
Toledo
Country [41] 0 0
Switzerland
State/province [41] 0 0
Basel
Country [42] 0 0
Switzerland
State/province [42] 0 0
Luzern
Country [43] 0 0
United Kingdom
State/province [43] 0 0
Wales
Country [44] 0 0
United Kingdom
State/province [44] 0 0
Cardiff
Country [45] 0 0
United Kingdom
State/province [45] 0 0
London
Country [46] 0 0
United Kingdom
State/province [46] 0 0
Oxford
Country [47] 0 0
United Kingdom
State/province [47] 0 0
Plymouth

Funding & Sponsors
Primary sponsor type
Commercial sector/industry
Name
Blueprint Medicines Corporation
Address
Country

Ethics approval
Ethics application status

Summary
Brief summary
This is a randomized, double-blind, placebo-controlled, Phase 2/3 study comparing the efficacy and safety of elenestinib (BLU-263) + best supportive care (BSC) with placebo + BSC in patients with indolent systemic mastocytosis (ISM) whose symptoms are not adequately controlled by BSC. Parts 1 and 2 will enroll patients with ISM. Patients enrolled in Part 1 or Part 2 will roll over onto Part 3 to receive treatment with elenestinib in an open-label fashion following completion of the earlier Part. Part M will enroll patients with monoclonal mast cell activation syndrome (mMCAS). Part S will enroll participants with smoldering systemic mastocytosis (SSM). The study also includes PK groups that will enroll patients with ISM.
Trial website
https://clinicaltrials.gov/study/NCT04910685
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 0 0
Address 0 0
Country 0 0
Phone 0 0
Fax 0 0
Email 0 0
Contact person for public queries
Name 0 0
Blueprint Medicines
Address 0 0
Country 0 0
Phone 0 0
617-714-6707
Fax 0 0
Email 0 0
[email protected]
Contact person for scientific queries



Summary Results

For IPD and results data, please see https://clinicaltrials.gov/study/NCT04910685