Clinical trial • Phase II • Haematology | Rare Disease
avapritinib for Indolent systemic mastocytosis | Systemic mastocytosis
Phase II trial of avapritinib for Indolent systemic mastocytosis | Systemic mastocytosis.
Overview
- Trial Therapeutic Area
- Haematology | Rare Disease
- Trial Disease
- Indolent systemic mastocytosis | Systemic mastocytosis
- Trial Stage
- Phase II
- Drug Modality
- Small molecule
- Orphan Drug
- Yes
Key dates
- Initial CTIS Submission Date
- 05-09-2024
- First CTIS Authorization Date
- 11-10-2024
Trial design
Randomised, placebo (avapritinib placebo tablets) - placebo control arm; (investigational product: avapritinib oral film-coated tablet, sponsor code blu-285; maximum daily dose listed as 100 mg)., adaptive Phase II trial across 19 sites in Spain, France, Sweden and others.
- Randomised
- Yes
- Comparator
- Placebo (Avapritinib Placebo Tablets) - placebo control arm; (investigational product: Avapritinib oral film-coated tablet, sponsor code BLU-285; maximum daily dose listed as 100 mg).
- Adaptive
- True - Part 1 is a dose-finding component to determine the RP2D (dose-escalation to establish recommended Phase 2 dose).
- Single Multiple Or Escalation Dose Combined
- Yes
- Target Sample Size
- 137
Eligibility
Recruits 137 Vulnerable population selected (isVulnerablePopulationSelected = true). All participants must be ≥ 18 years and "must be able to give written informed consent" (inclusion criterion). No assent procedures or minor-specific consent documents are described in the provided record..
- Pregnancy Exclusion
- 15. Pregnant women, as documented by a β-hCG pregnancy test consistent with pregnancy obtained within 7 days before the first dose of study drug.
- Vulnerable Population
- Vulnerable population selected (isVulnerablePopulationSelected = true). All participants must be ≥ 18 years and "must be able to give written informed consent" (inclusion criterion). No assent procedures or minor-specific consent documents are described in the provided record.
Inclusion criteria
- {"criterion_text":"- 1. Patients must be ≥ 18 years of age.\n- 2. Patient must have SM, confirmed by Central Pathology Review of BM biopsy, and central review of B- and C-findings by WHO diagnostic criteria.\n- 3. Patient must have moderate-to- severe symptoms based on minimum mean TSS over the 14-day eligibility screening period for assessment of TSS. Minimum TSS for eligibility is ≥ 28.\n- 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: H1 blockers, H2 blockers, proton-pump inhibitors, leukotriene inhibitors, cromolyn sodium, corticosteroids, or omalizumab.\n- 5. The patient's symptomatic SM therapies (e.g., H1 and H2 blockers) must be stable (same dose, no new medications ≥14 days before beginning the 14-day ISM-SAF eligibility TSS assessment).\n- 6. 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 ISM-SAF eligibility TSS assessment.\n- 7. Patient must have an ECOG-PS of 0 to 2.\n- 8. Patient must be able to give written informed consent."}
Exclusion criteria
- {"criterion_text":"- 1. Patient has been diagnosed with any of the following WHO SM subclassifications: Cutaneous mastocytosis only, SM-AHN, SSM, ASM, MCL, MC sarcoma.\n- 10. Patient has a history of a cerebrovascular accident or transient ischemic attacks within 12 months before the first dose of study drug.\n- 11. Patient has a known risk or recent history (12 months before the first dose of study drug) of ICB (eg, brain aneurysm).\n- 12. Patient has a primary brain malignancy or metastases to the brain.\n- 13. Patient has clinically significant, uncontrolled cardiovascular disease, including Grade III or Grade IV congestive heart failure greater than New York Heart Association classification II; myocardial infarction or unstable angina within the previous 6 months; clinically significant, uncontrolled arrhythmias, or uncontrolled hypertension.\n- 14. Female patients who are unwilling, if not postmenopausal or surgically sterile, to abstain from sexual intercourse or employ highly effective contraception during the study drug administration period and for at least 6 weeks after the last dose of study drug. Men who are unwilling, if not surgically sterile, to abstain from sexual intercourse or employ highly effective contraception during the study drug administration period and for at least 6 weeks after the last dose of study drug.\n- 15. Pregnant women, as documented by a β-hCG pregnancy test consistent with pregnancy obtained within 7 days before the first dose of study drug.\n- 16. Women who are breastfeeding.\n- 2. Patient has been diagnosed with another myeloproliferative disorder.\n- 3. Patient has any of the following organ damage C-findings attributable to SM: Cytopenia, Hepatomegaly with ascites and impaired liver function, Palpable splenomegaly with hypersplenism, Malabsorption with hypoalbuminemia and significant weight loss, Skeletal lesions: large osteolytic lesions with pathologic fractures, Life-threatening organ damage in other organ systems that is caused by MC infiltration in tissues.\n- 4. Patient meets any of the following laboratory criteria: Aspartate aminotransferase or alanine aminotransferase > 3.0 × ULN, Total bilirubin > 1.5 × ULN; > 3.0 × ULN if due to Gilbert's disease. (In the case of Gilbert's disease, a direct bilirubin > 2.0 × ULN is an exclusion.) Albumin < 1 × LLN, eGFR < 30 mL/min/1.73 m^2 or creatinine clearance or creatinine > 1.5 × ULN Absolute neutrophil count < 1.5 × 10^9/L, Hemoglobin < 10 g/dL, Platelet count < 100,000/μL\n- 5. Patient has received any of the following medications, therapies, or procedures in the timeframes listed: Any prior treatment with avapritinib, Any TKI, including but not limited to masitinib and midostaurin, or investigational agent for < 14 days or 5 half-lives of the drug (whichever is longer) before beginning the 14-day ISM-SAF eligibility TSS assessment, Any antineoplastic drug therapy < 28 days or 5 half-lives of the drug (whichever is longer) before beginning the 14- day ISM-SAF eligibility TSS assessment, Radiotherapy or PUVA therapy < 14 days before beginning the 14-day ISM-SAF eligibility TSS assessment, Any hematopoietic growth factor < 14 days before beginning the 14-day ISM-SAF eligibility TSS assessment, Any major surgical procedure < 14 days before starting the ISM-SAF for determination of eligibility.\n- 6. Patient requires therapy with a concomitant medication that is a strong inhibitor, strong inducer, or moderate inducer of CYP3A4 (see Appendix 9).\n- 7. Patient has a history of a malignancy that has been diagnosed or required therapy within 3 years before the first dose of study drug. Patients with a prior or concurrent malignancy whose natural history or treatment does not have the potential to interfere with the safety or efficacy assessment of the investigational agent may be included after approval by medical monitor.\n- 8. Patient has a QTcF > 480 msec.\n- 9. Patient has a history of a seizure disorder (eg, epilepsy) or requires antiseizure medication."}
Endpoints
Primary endpoints
- {"endpoint_text":"- Part 1 •The RP2D in patients with ISM.\n- Part 2 •Mean change in ISM-SAF TSS, from Baseline to C7D1.\n- Part 3 •The long-term safety and efficacy of avapritinib.","definition_or_measurement_approach":"Part 1: determination of RP2D (recommended Phase 2 dose) in Part 1 (dose-finding cohort). Part 2: mean change in ISM-SAF TSS from Baseline to Cycle 7 Day 1 compared to placebo using the ISM-SAF instrument. Part 3: assessment of long-term safety and efficacy via safety monitoring and efficacy assessments over the long-term treatment period."}
Secondary endpoints
- {"endpoint_text":"- • Change in measures of mast cell burden: serum tryptase, KIT D816V allele burden in blood, bone marrow mast cells.\n- • Change in best supportive care usage.\n- • Change in MC-QoL, PGIS, SF-12, PGIC, and EQ-5D-5L.\n- • Safety and tolerability of avapritinib, as assessed by AEs, vital signs, electrocardiograms, and laboratory tests.\n- • Pharmacokinetics of avapritinib (Part 1 and 2 only)","definition_or_measurement_approach":"Mast cell burden: measured by serum tryptase, KIT D816V allele fraction in peripheral blood, and bone marrow mast cell assessment. Supportive care usage captured as change in best supportive care. Patient-reported outcomes captured via MC-QoL, PGIS, SF-12, PGIC, EQ-5D-5L instruments. Safety via adverse events, vital signs, ECGs, laboratory tests. PK assessed in Parts 1 and 2."}
Recruitment
- Planned Sample Size
- 137
- Recruitment Window Months
- 100
- Consent Approach
- Participants must provide written informed consent themselves (inclusion criterion: "Patient must be able to give written informed consent"). Multiple country-specific ICFs are included in the submission (documents in English and in-country translations such as Spanish, French, Dutch, Swedish, Italian, Norwegian, German, Danish and local variants are present among submitted ICF documents). No assent procedures for minors are described; minimum age is ≥18.
Geography
- Total Number Of Sites
- 19
- Total Number Of Participants
- 114
Spain
- Earliest CTIS Part Ii Submission Date
- 18-09-2024
- Latest Decision Or Authorization Date
- 21-04-2026
- Number Of Sites
- 2
- Number Of Participants
- 17
Sites
- Site Name
- Hospital Virgen Del Valle
- Department Name
- Instituto de Estudios de Mastocitosis de Castilla La Mancha
- Contact Person Name
- Ivan Alvarez-Twose
- Contact Person Email
- iavana@sescam.jccm.es
- Site Name
- Hospital Universitari Vall D Hebron
- Department Name
- Internal Medice
- Contact Person Name
- Mar Guilarte Clavero
- Contact Person Email
- mguilarte@vhebron.net
France
- Earliest CTIS Part Ii Submission Date
- 18-09-2024
- Latest Decision Or Authorization Date
- 22-04-2026
- Number Of Sites
- 3
- Number Of Participants
- 17
Sites
- Site Name
- Hopitaux Universitaires Pitie Salpetriere
- Department Name
- Service de Dermatologie
- Contact Person Name
- Stephane BARETE
- Contact Person Email
- stephane.barete@aphp.fr
- Site Name
- Centre Hospitalier Universitaire De Toulouse
- Department Name
- Service de Dermatologie
- Contact Person Name
- Cristina LIVIDEANU
- Contact Person Email
- livideanu.c@chu-toulouse.fr
- Site Name
- Centre Hospitalier Regional De Marseille
- Department Name
- Service de Dermatologie et Cancerologie Cutanee
- Contact Person Name
- Caroline GAUDY-MARQUESTE
- Contact Person Email
- caroline.gaudy@ap-hm.fr
Sweden
- Earliest CTIS Part Ii Submission Date
- 18-09-2024
- Latest Decision Or Authorization Date
- 22-04-2026
- Number Of Sites
- 2
- Number Of Participants
- 3
Sites
- Site Name
- Karolinska University Hospital
- Department Name
- Hematologimottagningen R51
- Contact Person Name
- Johanna Ungerstedt
- Contact Person Email
- johanna.ungerstedt@ki.se
- Site Name
- Uppsala University Hospital
- Department Name
- Hematologmottagningen/101A
- Contact Person Name
- Mattias Mattsson
- Contact Person Email
- mattias.mattsson@akademiska.se
Netherlands
- Earliest CTIS Part Ii Submission Date
- 18-09-2024
- Latest Decision Or Authorization Date
- 30-04-2026
- Number Of Sites
- 2
- Number Of Participants
- 18
Sites
- Site Name
- Erasmus Universitair Medisch Centrum Rotterdam (Erasmus MC)
- Department Name
- Immunology
- Contact Person Name
- Paulus van Daele
- Contact Person Email
- p.l.a.vandaele@eramsusmc.nl
- Site Name
- Universitair Medisch Centrum Groningen
- Department Name
- Allergology
- Contact Person Name
- Hanneke Oude Elberink
- Contact Person Email
- j.n.g.oude.elberink@umcg.nl
Belgium
- Earliest CTIS Part Ii Submission Date
- 18-09-2024
- Latest Decision Or Authorization Date
- 12-05-2026
- Number Of Sites
- 1
- Number Of Participants
- 10
Sites
- Site Name
- Antwerp University Hospital
- Department Name
- Department of Immunology-allergology
- Contact Person Name
- Vito Sabato
- Contact Person Email
- vito.sabato@uza.be
Denmark
- Earliest CTIS Part Ii Submission Date
- 18-09-2024
- Latest Decision Or Authorization Date
- 17-04-2026
- Number Of Sites
- 1
- Number Of Participants
- 1
Sites
- Site Name
- Odense University Hospital
- Department Name
- ORCA/ Allergicentret Hudafdeling I og Allergicenter
- Contact Person Name
- Sigurd Broesby-Olsen
- Contact Person Email
- OUH.ODE.I.Blueprint@rsyd.dk
Norway
- Earliest CTIS Part Ii Submission Date
- 18-09-2024
- Latest Decision Or Authorization Date
- 20-04-2026
- Number Of Sites
- 1
- Number Of Participants
- 8
Sites
- Site Name
- Oslo University Hospital HF
- Department Name
- Rikshospitalet Seksjon Klinisk Forskningspost
- Contact Person Name
- Ingunn Dybedal
- Contact Person Email
- idybedal@ous-hf.no
Germany
- Earliest CTIS Part Ii Submission Date
- 18-09-2024
- Latest Decision Or Authorization Date
- 22-04-2026
- Number Of Sites
- 5
- Number Of Participants
- 34
Sites
- Site Name
- Universitaetsklinikum Schleswig-Holstein AöR
- Department Name
- Haematologie- Onkologie
- Contact Person Name
- Friederike Wortmann
- Contact Person Email
- friederike.wortmann@uksh.de
- Site Name
- Charite Universitaetsmedizin Berlin KöR
- Department Name
- Institut für Allergologie
- Contact Person Name
- Frank Siebenhaar
- Contact Person Email
- frank.siebenhaar@charite.de
- Site Name
- Universitaetsklinikum Aachen AöR
- Department Name
- Klinik für Haematologie Onkologie Haemostaseologie und Stammzelltransplantation
- Contact Person Name
- Jens Panse
- Contact Person Email
- jpanse@ukaachen.de
- Site Name
- Universitaetsklinikum Mannheim GmbH
- Department Name
- Medizinische Klinik III
- Contact Person Name
- Andreas Reiter
- Contact Person Email
- andreas.reiter@medma.uni-heidelberg.de
- Site Name
- University Medical Center Hamburg-Eppendorf
- Department Name
- Abteilung für Onkologie und Haematologie
- Contact Person Name
- Philippe Schafhausen
- Contact Person Email
- schafhausen@uke.de
Italy
- Earliest CTIS Part Ii Submission Date
- 18-09-2024
- Latest Decision Or Authorization Date
- 20-04-2026
- Number Of Sites
- 2
- Number Of Participants
- 6
Sites
- Site Name
- Centro Ricerche Cliniche Di Verona S.r.l.
- Department Name
- UOC Allergologia e asma center
- Contact Person Name
- Elisa Olivieri
- Contact Person Email
- elisa.olivieri2@aovr.veneto.it
- Site Name
- Azienda Ospedaliera Universitaria San Giovanni Di Dio E Ruggi d'Aragona
- Department Name
- Unita’ Operativa Complessa di Immunologia Clinica e Reumatologia
- Contact Person Name
- Massimo Triggiani
- Contact Person Email
- mtriggiani@unisa.it
Sponsor
Primary sponsor
- Full Name
- Blueprint Medicines Corp.
- Organisation Type
- Pharmaceutical company
- Country Of Registered Address
- United States
Contract research organisations
- Name
- Syneos Health Netherlands B.V.
- Name
- PPD (UK) Limited
- Responsibilities
- PV reporting
- Name
- Endpoint Clinical Inc.
- Name
- Biotel Research LLC
- Responsibilities
- Imaging services
- Name
- Signant Health Global LLC
- Responsibilities
- E-data capture - QOL questionnaire
Third parties
- {"country":"United States","full_name":"Arup Laboratories Inc.","duties_or_roles":"Central Pathology Lab- Analysis of bone marrow samples for SM diagnosis and biomarker analysis","organisation_type":"Laboratory/Research/Testing facility"}
- {"country":"United States","full_name":"Medpace Reference Laboratories LLC","duties_or_roles":"Central lab for tryptase & sample management","organisation_type":"Laboratory/Research/Testing facility"}
- {"country":"United Kingdom","full_name":"Mde Services Group Limited","duties_or_roles":"Patient Reimbursement","organisation_type":"Hospital/Clinic/Other health care facility"}
- {"country":"United Kingdom (Northern Ireland)","full_name":"Almac Clinical Services Limited","duties_or_roles":"IMP Packaging and distribution - EU QP Release","organisation_type":"Pharmaceutical company"}
- {"country":"Ireland","full_name":"Almac Clinical Services (Ireland) Limited","duties_or_roles":"• IMP Packaging and distribution • EU QP Release","organisation_type":"Pharmaceutical company"}
- {"country":"United States","full_name":"Endpoint Clinical Inc.","duties_or_roles":"","organisation_type":"Pharmaceutical company"}
- {"country":"United States","full_name":"Biotel Research LLC","duties_or_roles":"Imaging services","organisation_type":"Pharmaceutical company"}
- {"country":"United States","full_name":"Frontage Laboratories Inc.","duties_or_roles":"PK analyses","organisation_type":"Pharmaceutical company"}
- {"country":"United States","full_name":"Canfield Scientific Inc.","duties_or_roles":"Skin photography","organisation_type":"Pharmaceutical company"}
- {"country":"United States","full_name":"Molecularmd Corp.","duties_or_roles":"DNA Mutation Analysis","organisation_type":"Pharmaceutical company"}
- {"country":"United States","full_name":"Signant Health Global LLC","duties_or_roles":"E-data capture - QOL questionnaire","organisation_type":"Pharmaceutical company"}
- {"country":"Netherlands","full_name":"Syneos Health Netherlands B.V.","duties_or_roles":"","organisation_type":"Pharmaceutical company"}
- {"country":"United Kingdom","full_name":"PPD (UK) Limited","duties_or_roles":"PV reporting","organisation_type":"Pharmaceutical company"}
Investigational products
- Investigational Product Name
- Avapritinib
- Active Substance
- avapritinib
- Modality
- Small molecule
- Routes Of Administration
- Oral
- Route
- Oral
- Authorisation Status
- Authorised
- Orphan Designation
- Yes
- Maximum Dose
- 100 mg daily
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