A Study of Avapritinib in Patients with Indolent and 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] - Hemic and Lymphatic Diseases [C15]

Trial duration

27 Feb 2019 → ongoing

Decision date (initial)

2024-10-14

Transition trial

Yes

Low-intervention

No

Rare-disease indication

Yes

Vulnerable population

Yes

Funding sources

Blueprint Medicines Corporation, United States

External identifiers

EU CT number

2024-512585-34-00

EudraCT number

2018-000588-99

ClinicalTrials.gov

NCT03731260

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

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

Part 1- To determine the RP2D of avapritinib in patients with ISM for use in Part 2 and Part 3 of the study.
Part 2- To determine mean change in ISM-SAF TSS from baseline to C7D1, compared to placebo.
Part 3- To assess the long-term safety and efficacy of avapritinib in ISM patients.

Secondary objectives 1

1. Key Secondary (Part2 Only) To determine the proportion of avapritinib-treated patients with ISM, from baseline to C7D1, compared to placebo: - with a ≥50% reduction in serum tryptase - with a ≥50% reduction in peripheral blood KIT D816V allele fraction or undetectable (<0.02%) for patients with detectable mutation at Baseline - achieving ≥50% reduction in ISM-SAF TSS - achieving ≥30% reduction in ISM-SAF TSS - with a ≥50% reduction in bone marrow mast cells or no aggregates for patients with aggregates at Baseline Additional Secondary Assess change in: - measures of mast cell burden in each treatment cohort (serum tryptase, KIT D816V allele burden in blood, bone marrow mast cells) - best supportive care usage for SM symptoms Assess change in other Patient-Reported Outcomes and Quality of Life measures Assess the safety and tolerability of avapritinib, as assessed by AEs, vital signs, electrocardiograms, and laboratory tests. Assess the PK of avapritinib (Part 1 & 2 only)

Conditions and MedDRA coding

Indolent Systemic Mastocytosis (ISM)

Regulatory references

Scientific advice from competent authorities

European Medicines Agency

Plan to share IPD

Yes

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 8

1. 1. Patients must be ≥ 18 years of age.
2. 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.
3. 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.
4. 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.
5. 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).
6. 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.
7. 7. Patient must have an ECOG-PS of 0 to 2.
8. 8. Patient must be able to give written informed consent.

Exclusion criteria 16

1. 1. Patient has been diagnosed with any of the following WHO SM subclassifications: Cutaneous mastocytosis only, SM-AHN, SSM, ASM, MCL, MC sarcoma.
2. 2. Patient has been diagnosed with another myeloproliferative disorder.
3. 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.
4. 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
5. 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.
6. 6. Patient requires therapy with a concomitant medication that is a strong inhibitor, strong inducer, or moderate inducer of CYP3A4 (see Appendix 9).
7. 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.
8. 8. Patient has a QTcF > 480 msec.
9. 9. Patient has a history of a seizure disorder (eg, epilepsy) or requires antiseizure medication.
10. 10. Patient has a history of a cerebrovascular accident or transient ischemic attacks within 12 months before the first dose of study drug.
11. 11. Patient has a known risk or recent history (12 months before the first dose of study drug) of ICB (eg, brain aneurysm).
12. 12. Patient has a primary brain malignancy or metastases to the brain.
13. 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.
14. 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.
15. 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.
16. 16. Women who are breastfeeding.

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 1

1. Part 1 •The RP2D in patients with ISM. Part 2 •Mean change in ISM-SAF TSS, from Baseline to C7D1. Part 3 •The long-term safety and efficacy of avapritinib.

Secondary endpoints 1

1. • Change in measures of mast cell burden: serum tryptase, KIT D816V allele burden in blood, bone marrow mast cells. • Change in best supportive care usage. • Change in MC-QoL, PGIS, SF-12, PGIC, and EQ-5D-5L. • Safety and tolerability of avapritinib, as assessed by AEs, vital signs, electrocardiograms, and laboratory tests. • Pharmacokinetics of avapritinib (Part 1 and 2 only)

Investigational products

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

Test 2

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 13

Locations

9 EU/EEA countries · 19 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 71 files

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

Application history

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