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JOURNAL ONKOLOGIE – STUDIE

(HARBOR) Study to Evaluate Efficacy and Safety of BLU-263 Versus Placebo in Patients With Indolent Systemic Mastocytosis

Rekrutierend

NCT-Nummer:
NCT04910685

Studienbeginn:
November 2021

Letztes Update:
23.10.2023

Wirkstoff:
BLU-263, Placebo

Indikation (Clinical Trials):
Mastocytosis, Mastocytosis, Systemic, Mast Cell Activation Syndrome, Mast Cell Activation Disorders

Geschlecht:
Alle

Altersgruppe:
Alle

Phase:
-

Sponsor:
Blueprint Medicines Corporation

Collaborator:
-

Kontakt

Studienlocations
(3 von 49)

Universitätsklinikum RWTH Aachen Klinik für Hämatologie, Onkologie, Hämostaseologie und Stammzelltransplantation
Aachen
(Nordrhein-Westfalen)
GermanyRekrutierend» Google-Maps
Charité - Universitätsmedizin Berlin Institute of Allergology
12203 Berlin
(Berlin)
GermanyRekrutierend» Google-Maps
University Clinic Erlangen
91054 Erlangen
(Bayern)
GermanyRekrutierend» Google-Maps
University Clinic Hamburg Eppendorf
20246 Hamburg
(Hamburg)
GermanyRekrutierend» Google-Maps
Universitätsmedizin Mannheim III. Medizinische Klinik Universität Heidelberg Medizinische Fakultät Mannheim
68167 Mannheim
(Baden-Württemberg)
GermanyRekrutierend» Google-Maps
University of Alabama at Birmingham
35294 Birmingham
United StatesRekrutierend» Google-Maps
Stanford Cancer Institute
94305 Palo Alto
United StatesRekrutierend» Google-Maps
Brigham and Women's Hospital
02115 Boston
United StatesRekrutierend» Google-Maps
Michigan Medicine University of Michigan
48109 Ann Arbor
United StatesRekrutierend» Google-Maps
Roswell Park Cancer Institute
14263 Buffalo
United StatesRekrutierend» Google-Maps
Columbia University Medical Center
10032 New York
United StatesRekrutierend» Google-Maps
University of Cincinnati Medical Center
45219 Cincinnati
United StatesRekrutierend» Google-Maps
The University of Texas, MD Anderson Cancer Center
77030 Houston
United StatesRekrutierend» Google-Maps
Huntsman Cancer Institute, University of Utah
84112 Salt Lake City
United StatesRekrutierend» Google-Maps
Princess Alexandra Hospital
Woolloongabba
AustraliaRekrutierend» Google-Maps
Kepler Universitatsklinikum, Med Campus III. Clinic of Internal Medicine 3 - Hematology and Oncology
4021 Linz
AustriaRekrutierend» Google-Maps
Hôpital de la Pitié Salpétrière
75013 Paris
FranceRekrutierend» Google-Maps
Hôpital Necker - Départementd 'HématologieA dultes
75015 Paris
FranceRekrutierend» Google-Maps
Dipartimentod i Oncoematologia Istituto Scientifico Romagnolop er lo studio e la cura dei tumori (IRST)- IRCCS
47014 Meldola
ItalyRekrutierend» Google-Maps
SOD Ematologia (Ambulatori)- AOUC Azienda Ospedaliero Universitaria Careggi
50134 Firenze
ItalyRekrutierend» Google-Maps
Unita Operativa di Ematologia AOU Policlinico S. Orsola-Malpighi
40138 Bologna
ItalyRekrutierend» Google-Maps
S.C. Ematologia Fondazione I.R.C.C.S. Policlinico San Matteo
27100 Pavia
ItalyRekrutierend» Google-Maps
S.S.D. Immunologia Clinica e Allergologia Azienda Ospedaliera Universitaria San Giovanni di Dio e Ruggi d'Aragona
84131 Salerno
ItalyRekrutierend» Google-Maps
Unità Operativa di Allergologia Azienda Ospedaliera Universitaria Integrata di Verona
37126 Verona
ItalyRekrutierend» Google-Maps
University Medical Center Groningen
9713 GZ Groningen
NetherlandsRekrutierend» Google-Maps
Centro Hospitalar de Lisboa Central, E.P.E. - Hospital de Santo Antonio dos Capuchos
1169-050 Lisbon
PortugalRekrutierend» Google-Maps
CHUPorto, EPE - Hospital de Santo António
4099-001 Porto
PortugalRekrutierend» Google-Maps
Centro Hospitalar Universitario Sao Joao, E.P.E.
4200-139 Porto
PortugalRekrutierend» Google-Maps
Hospital Universitario Vall d'Hebron
Barcelona
SpainRekrutierend» Google-Maps
Hospital Universitario Ramon y Cajal
28034 Madrid
SpainRekrutierend» Google-Maps
Hospital Virgen del Valle - Instituto de Estudios de Mastocitosis de Castilla-La Mancha
45071 Toledo
SpainRekrutierend» Google-Maps
University Hospital Basel
C-4031 Basel
SwitzerlandRekrutierend» Google-Maps
University Hospital of Wales
CF14 4XW Cardiff
United KingdomRekrutierend» Google-Maps
Cancer and Haematology Centre
OX3 7LE Oxford
United KingdomRekrutierend» Google-Maps
Alle anzeigen

Studien-Informationen

Brief Summary:

This is a randomized, double-blind, placebo-controlled, Phase 2/3 study comparing the

efficacy and safety of 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 BLU-263 in an open-label fashion following

completion of the earlier Part. Part M will enroll patients with monoclonal mast cell

activation syndrome (mMCAS). The study also includes PK groups that will enroll patients with

ISM.

Ein-/Ausschlusskriterien

Key Inclusion Criteria:

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.

Key Exclusion Criteria:

- 1. Patient has been diagnosed with any of the following WHO systemic mastocytosis (SM)

sub-classifications: cutaneous mastocytosis only, smoldering SM, SM with associated

hematologic neoplasm, 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.

Studien-Rationale

Primary outcome:

1. Part 1: Recommended Dose (RD) in patients with ISM (Time Frame - 3 months):
Selection of the RD to be used in Part 2, Part 3 and Part M of the study

2. Part 2: Proportion of responders, defined as ≥30% reduction in ISM-Symptom in Assessment Form (ISM-SAF) Total Symptom Score (TSS) (Time Frame - 6 months):
Response rate in patients with ISM

3. Part 3: Long-term safety and tolerability of BLU-263 as assessed by the number of adverse events and serious adverse events (Time Frame - up to 5 years)

4. Part 3: Mean change in Indolent Systemic Mastocytosis-Symptom Assessment Form (ISM-SAF) Total Symptom Score (TSS) (Time Frame - up to 5 years):
The ISM-SAF has a scale of 0-110. A decrease in score corresponds to improvement in symptoms

Secondary outcome:

1. Part 1: Mean change in measures of mast cell burden (Time Frame - 3 Months)

2. Part 1: Mean change in Indolent Systemic Mastocytosis-Symptom Assessment Form (ISM-SAF) Total Symptom Score (TSS) (Time Frame - 3 Months):
The ISM-SAF has a scale of 0-110. A decrease in score corresponds to improvement in symptoms

3. Part 1: Mean change in Indolent Systemic Mastocytosis-Symptom Assessment Form (ISM-SAF) individual symptom scores (Time Frame - 3 months):
Each symptom in the ISM-SAF has a scale of 0-10. A decrease in score corresponds to improvement in symptoms

4. Part 1: Time to achieve 30% reduction inIndolent Systemic Mastocytosis-Symptom Assessment Form (ISM-SAF) scores (Time Frame - 3 months):
Time to achieve a 30% reduction in scores generated by the ISM-SAF. The ISM-SAF uses a score from 0-110 and a lower score represents lower symptom burden

5. Part 2: Proportion of patients with a ≥50% reduction in serum tryptase (Time Frame - 6 months)

6. Part 2: The proportion of patients who achieve at least a 50% reduction in peripheral blood KIT D816V allele fraction, or a reduction to undetectable levels. (Time Frame - 6 months)

7. Part 2: Mean change in Indolent Systemic Mastocytosis-Symptom Assessment Form (ISM-SAF) Total Symptom Score (TSS) (Time Frame - 6 months):
The ISM-SAF has a scale of 0-110. A decrease in score corresponds to improvement in symptoms

8. 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 (Time Frame - 6 months)

9. Part 2: Mean change in measures of mast cell burden (Time Frame - 6 months)

10. Part 2: Change in number of best supportive care medications (Time Frame - 6 Months)

11. Part 2: Mean change in Indolent Systemic Mastocytosis-Symptom Assessment Form (ISM-SAF) individual symptom scores (Time Frame - 6 months):
Each symptom in the ISM-SAF has a scale of 0-10. A decrease in score corresponds to improvement in symptoms

12. Part 2: Change in Indolent Systemic Mastocytosis-Symptom Assessment Form (ISM-SAF) leading symptom score (Time Frame - 6 months):
Each symptom in the ISM-SAF has a scale of 0-10. A decrease in score corresponds to improvement in symptoms

13. Part 2: Time to achieve 30% reduction in Indolent Systemic Mastocytosis-Symptom Assessment Form (ISM-SAF) scores (Time Frame - 6 months):
Time to achieve a 30% reduction in scores generated by the ISM-SAF. The ISM-SAF uses a score from 0-10 and a lower score represents lower symptom burden

14. Part 2: Mean change in the Mast Cell Quality of Life (MC-QoL) score (Time Frame - 6 months):
The MC-QoL has a scale of 0-100, higher numbers represent more severe impairment to quality of life.

15. Part 2: Safety of BLU-263 as assessed by number of adverse events and serious adverse events (Time Frame - up to 5 years)

16. Part 3: Mean change in measures of mast cell burden (Time Frame - approximately 5 years)

17. Part 3: Change in number of best supportive care medications (Time Frame - approximately 5 years)

18. Part 3: Mean change in Indolent Systemic Mastocytosis-Symptom Assessment Form (ISM-SAF) individual symptom score (Time Frame - approximately 5 years):
Each symptom in the ISM-SAF has a scale of 0-10. A decrease in score corresponds to improvement in symptoms

19. Part 3: Change in Indolent Systemic Mastocytosis-Symptom Assessment Form (ISM-SAF) leading symptom score (Time Frame - approximately 5 years):
Each symptom in the ISM-SAF has a scale of 0-10. A decrease in score corresponds to improvement in symptoms

20. Part 3: Mean change in the Mast Cell Quality of Life (MC-QoL) score (Time Frame - approximately 5 years):
The MC-QoL has a scale of 0-100, higher numbers represent more severe impairment to quality of life.

21. Part 3: Time to achieve 30% reduction in Indolent Systemic Mastocytosis-Symptom Assessment Form (ISM-SAF) Scores (Time Frame - 12 months):
Time to achieve a 30% reduction in scores generated by the ISM-SAF. The ISM-SAF uses a score from 0-110 and a lower score represents lower symptom burden

Studien-Arme

  • Experimental: (Part 1) BLU-263 Dose 1 + BSC
    Patients will receive best supportive care (BSC) and Dose 1 of BLU-263 tablets. BSC will be determined on a per patient basis. BLU-263 will be administered orally, once daily until completion of Part 1.
  • Experimental: (Part 1) BLU-263 Dose 2 + BSC
    Patients will receive best supportive care (BSC) and Dose 2 of BLU-263 tablets. BSC will be determined on a per patient basis. BLU-263 will be administered orally, once daily until completion of Part 1.
  • Experimental: (Part 1) BLU-263 Dose 3 + BSC
    Patients will receive best supportive care (BSC) and Dose 3 of BLU-263 tablets. BSC will be determined on a per patient basis. BLU-263 will be administered orally, once daily until completion of Part 1.
  • Placebo Comparator: (Part 1) Placebo + BSC
    Patients will receive best supportive care (BSC) and matching placebo tablets. BSC will be determined on a per patient basis. Placebo will be administered orally, once daily until completion of Part 1
  • Experimental: (Part 2) BLU-263 RD + BSC
    Patients will receive best supportive care (BSC) and the recommended dose (RD) of BLU-263 tablets. BSC will be determined on a per patient basis. BLU-263 will be administered orally, once daily for approximately 24 weeks
  • Placebo Comparator: (Part 2) Placebo + BSC
    Patients will receive best supportive care (BSC) and matching placebo tablets. 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) BLU-263 RD + BSC
    Patients will receive best supportive care (BSC) and the recommended dose (RD) of BLU-263 tablet in an open-label fashion for up to 5 years.
  • Experimental: (Part M) BLU-263 RD + BSC
    Patients will receive best supportive care (BSC) and the recommended dose (RD) of BLU-263 tablets. BSC will be determined on a per patient basis. BLU-263 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 best supportive care (BSC) and Dose 2 or Dose 3 of BLU-263 tablets. BSC will be determined on a per patient basis. BLU-263 will be administered orally for the duration of participation in the study.

Geprüfte Regime

  • BLU-263:
    BLU-263 tablet
  • Placebo:
    Placebo Tablet

Quelle: ClinicalTrials.gov


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