A Study of Avapritinib in Patients with Advanced Systemic Mastocytosis

Phase 1

• Conditions: Advanced Systemic Mastocytosis (AdvSM); MedDRA version: 20.0Level: LLTClassification code 10056453Term: Aggressive systemic mastocytosisSystem Organ Class: 100000004864; Therapeutic area: Diseases [C] - Cancer [C04]

• Registration Number: EUCTR2017-004836-13-AT
• Lead Sponsor: Blueprint Medicines Corporation

Brief Summary

Not available

Detailed Description

Not available

Study Timeline

• Results First Posted: 1900-01-01
• Study Start: 2020-01-07
• Last Update Posted: 12 July 2021

Recruitment & Eligibility

• Status: Authorised-recruitment may be ongoing or finished
• Sex: All
• Target Recruitment: 103

Inclusion Criteria

1. Patients who are = 18 years of age.
2. Patients must have 1 of the following diagnoses as confirmed by WHO diagnostic criteria (Appendix 4, Appendix 5, and Appendix 6). Before enrollment, the SSC must confirm the diagnosis of AdvSM (based on Central Pathology Laboratory assessment of BM).
o ASM.
o SM-AHN.

The AHN must be myeloid, with the following exceptions that are excluded:
• AML.
• Myelodysplastic syndrome that is very high- or high-risk, as defined by the International Prognostic Scoring System for Myelodysplastic Syndromes (Greenberg et al, 2012).
• A myeloid AHN with = 10% BM or PB blasts.
• Philadelphia chromosome-positive malignancies.

Incidental indolent, low-grade lymphoid AHNs (eg, chronic lymphocytic leukemia) not requiring treatment are eligible.
o MCL, including diagnoses with an AHN component.
3. Patients with SM-AHN should have received prior treatment for the AHN component of disease if, in the opinion of the Investigator, such therapy was appropriate.
4. Patient must have a BM biopsy taken within 56 days of C1D1, assessed by the Central Pathology Laboratory.
5. Cohort 1 only: Patient must have at least 1 of the following measurable C-findings, per modified IWG-MRT-ECNM criteria, attributed to SM (Appendix 6, unless diagnosis is MCL, which does not require a C-finding). Laboratory abnormality C-findings should not be assessed until the required washout period from last cytoreductive therapy has been met. If a C-finding improves during the Screening period, prior to dosing, and no longer meets criteria for evaluability, it can no longer be counted as a C-finding. In addition,
• Patients must have documented evidence of mast cell aggregates in the bone marrow or other extracutaneous organ based on central pathology.
• Patient must be willing to have follow up biopsies of affected organ(s) to document response.
Measurable C-findings:
o Cytopenias:

• ANC < 1.0 × 10^9/L or
• Hemoglobin < 10 g/dL or
• Platelet count < 75 × 109/L.

NOTE: Cytopenias attributable to prior cytoreductive therapy or causes other than SM may not be used as C-findings.
o Symptomatic ascites or pleural effusion requiring medical intervention such as:

• Use of diuretics (Grade 2) or
• = 2 therapeutic paracenteses or thoracenteses (Grade 3) at least 28 days apart over the 12 weeks before

C1D-8 and 1 of the procedures is performed during the 6 weeks before C1D-8.
o = Grade 2 abnormalities in direct bilirubin (> 1.5 × upper limit of normal [ULN]), aspartate aminotransferase (AST; > 3.0 × ULN), alanine aminotransferase (ALT; > 3.0 × ULN), or alkaline phosphatase (> 2.5 × ULN) with 1 of the following present:

• Ascites or
• Clinically relevant portal hypertension or
• Liver MC infiltration that is biopsy-proven or
• No other identified cause of abnormal liver function.

o = Grade 2 hypoalbuminemia (< 3.0 g/dL).
o A spleen that is palpable = 5 cm below the left costal margin.
o Transfusion-dependent anemia defined as:

• Transfusion of = 6 units packed red blood cells (PRBCs) in the 12 weeks before C1D-8 and
• Most recent transfusion occurring during the 4 weeks before C1D-8 and
• Transfusion administered for hemoglobin = 8.5 g/dL and
• Reason for transfusion is not bleeding, hemolysis, or therapy-related.

6. Patient must have a serum tryptase = 20 ng/mL.
7. Patients receiving cytoreductive therapy within the preceding 12 weeks must have discontinued therapy due to disease progression, refractory disease, lack of efficacy, or intoleran

Exclusion Criteria

1. Patient has received prior treatment with avapritinib.
2. Patient has received any cytoreductive therapy (including midostaurin and other TKIs, hydroxyurea, azacitidine) or an investigational agent less than 14 days, and for cladribine, interferon alpha, pegylated interferon and any antibody therapy (eg, brentuximab vedotin) less than 28 days before obtaining screening BM biopsy for this study. If the patient has progressive disease and it is in the patient’s best interest to enroll in the study rapidly, cytoreductive therapy may be discontinued 1 day before the screening BM biopsy with approval from the Medical Monitor. Cytoreductive therapy may not be restarted during Screening or while on study.
3. Patient has received prior radiotherapy within 14 days before the screening BM biopsy, unless given to palliate specific sites of disease (eg, bone lesion).
4. Patient received any hematopoietic growth factor within 14 days of screening BM biopsy.
5. Patient requires therapy with a concomitant medication that is a strong inhibitor, strong inducer, or moderate inducer of CYP3A4 (Appendix 13).
6. Patient has had a major surgical procedure within 14 days of the first dose of study drug. Surgical procedures such as central venous catheter placement, BM biopsy, and feeding tube placement are considered minor surgical procedures.
7. Patient is a candidate for allogeneic hematopoietic stem cell transplantation for treatment of SM, in the opinion of the Investigator.
8. Patient has eosinophilia and known positivity for the FIP1L1-PGDFRA fusion, unless the patient has demonstrated relapse or PD on prior imatinib therapy. Patients with eosinophilia (> 1.5 × 10^9/L), who do not have a detectable KIT D816 mutation, must be tested for a PDGFRA fusion mutation by fluorescence in situ hybridization (FISH) or PCR.
9. Patient has history of another primary malignancy that has been diagnosed or required therapy within 3 years before the first dose of study drug.
10. Patient meets any of the following laboratory criteria:
o AST or ALT > 3.0 × ULN; no restriction if due to suspected liver infiltration by MCs.
o Bilirubin > 1.5 × ULN; no restriction if due to suspected liver infiltration by MCs or Gilbert’s disease. (In the case of Gilbert’s disease, a direct bilirubin > 2.0 × ULN would be an exclusion.)
o Estimated glomerular filtration rate (eGFR) < 30 mL/min/1.73m2 or creatinine> 1.5 × ULN.
oPlatelet count < 50,000/µL (within 4 weeks of the first dose of study drug) or receiving platelet transfusion(s)
11. Patient has a QT interval corrected using Fridericia’s formula (QTcF) > 480 msec.
12. Patient has a history of a seizure disorder (eg, epilepsy) or requirement for antiseizure medication.
13. Patient has a history of a cerebrovascular accident or transient ischemic attacks within 1 year before the first dose of study drug.
14. Patient has a known risk or recent history (12 months before the first dose of study drug) of intracranial bleeding (eg, brain aneurysm, concomitant vitamin K antagonist use).
15. Patient has a primary brain malignancy or metastases to the brain.
16. Patient has clinically significant, uncontrolled cardiovascular disease, including Grade III or IV congestive heart failure according to the New York Heart Association classification; myocardial infarction or unstable angina within the previous 6 months; clinically significant, uncontrolled arrhythmias; or uncontrolled hypertension.
17. Patient is unwilling or unable to comply wit

Study & Design

• Study Type: Interventional clinical trial of medicinal product
• Study Design: Not specified