(EXPLORER) Study of BLU-285 in Patients With Advanced Systemic Mastocytosis (AdvSM) and Relapsed or Refractory Myeloid Malignancies

A Phase 1 Study of BLU-285 in Patients With Advanced Systemic Mastocytosis (AdvSM) and Relapsed or Refractory Myeloid Malignancies

This is a Phase 1, open-label, dose-escalation study designed to evaluate the safety, tolerability, pharmacokinetics (PK), pharmacodynamics (PD) and antineoplastic activity of avapritinib (also known as BLU-285), administered orally (PO), in adult patients with advanced systemic mastocytosis and other relapsed or refractory myeloid malignancies. The study consists of 2 parts:, dose-escalation (Part 1) and expansion (Part 2).

Study Overview

• Status: Completed
• Conditions: Mast Cell Leukemia; Aggressive Systemic Mastocytosis; Systemic Mastocytosis-associated Hematologic Non-mast Cell Disease; Relapsed or Refractory Myeloid Malignancies
• Intervention / Treatment: Drug: Avapritinib

• Study Type: Interventional
• Enrollment (Actual): 86
• Phase: Phase 1

Contacts and Locations

Study Locations

• United Kingdom
  • Glasgow, United Kingdom, G12 0XL
    • Beatson West of Scotland Cancer Centre
  • London, United Kingdom, SE1 9RT
    • Guy's Hospital
• United States
  • California
    • Stanford, California, United States, 94305
      • Stanford Cancer Institute
  • Colorado
    • Denver, Colorado, United States, 80045
      • University of Colorado Cancer Center
  • Georgia
    • Atlanta, Georgia, United States, 30322
      • Emory University
  • Massachusetts
    • Boston, Massachusetts, United States, 02215
      • Dana Farber Cancer Institute
  • Michigan
    • Ann Arbor, Michigan, United States, 48109
      • University of Michigan Health System
  • New York
    • New York, New York, United States, 10029
      • Mount Sinai Hospital
  • Pennsylvania
    • Philadelphia, Pennsylvania, United States, 19104
      • University of Pennsylvania
  • Texas
    • Houston, Texas, United States, 77030
      • MD Anderson Cancer Center
  • Utah
    • Salt Lake City, Utah, United States, 84112
      • Huntsman Cancer Institute

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

For Part 1:Patients must have one of the following diagnoses based on World Heath Organization (WHO) diagnostic criteria:

• Aggressive systemic mastocytosis (ASM).
• Systemic mastocytosis with an associated hematologic neoplasm (SM-AHN) and at least 1 C-finding attributable to systemic mastocytosis (SM). The AHN must be myeloid, with the following exceptions that are excluded: Acute myeloid leukemia (AML), Myelodysplastic syndrome (MDS) that is very high- or high-risk as defined by the International prognostic scoring system for myelodysplastic syndromes (IPSS-R) and Philadelphia chromosome positive malignancies.
• Mast cell leukemia (MCL).
• Histologically- or cytologically- confirmed myeloid malignancy that is relapsed or refractory to standard treatments. AML, MDS that is very high- or high-risk as defined by the IPSS-R, and Philadelphia chromosome positive malignancies are excluded.
• Upon discussion with the sponsor, other relapsed or refractory, potentially avapritinib-responsive hematologic neoplasms (e.g., evidence of aberrant KIT or platelet derived growth factor receptor (PDGFR) signaling) may be considered for enrollment.

For Part 2, patients must have one of the following diagnoses, based on WHO diagnostic criteria:

• ASM.
• SM-AHN. The AHN must be myeloid, with the following exceptions that are excluded: AML, MDS that is very high- or high-risk as defined by the IPSS-R, and Philadelphia chromosome positive malignancies.
• MCL.

For Part 2, Cohort 2, patients must have at least 1 measurable C-finding per modified IWG-MRT-ECNM criteria at Baseline, attributed to SM unless diagnosis is MCL, which does not require a C-finding.

• Cytopenias: ANC < 1.0 × 10⁹/L or hemoglobin < 10 g/dL or platelet count < 75 × 10⁹/L.
• 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 study entry and 1 of the procedures is performed during the 6 weeks before study start (C1D1).
• ≥ 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 mast cell infiltration that is biopsy-proven or no other identified cause of abnormal liver function.
• ≥ Grade 2 hypoalbuminemia (< 3.0 g/dL).
• A spleen that is palpable ≥ 5 cm below the left costal margin.
• Transfusion-dependent anemia defined as: transfusion of ≥ 6 units packed red blood cells (PRBCs) in the 12 weeks before start of treatment (C1D1) and most recent transfusion occurring during the preceding 4 weeks and transfusion administered for hemoglobin ≤ 8.5 g/dL and reason for transfusion is not bleeding, hemolysis, or therapy-related.

Eastern Cooperative Oncology Group (ECOG) performance status of 0-3.

Exclusion Criteria:

• QT interval corrected using Fridericia's formula (QTcF) >480 milliseconds
• Platelet count <50,000/μL (within 4 weeks of the first dose of study drug) or receiving platelet transfusion(s)
• Absolute neutrophil count <500/μL
• Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) >3 x the upper limit of normal (ULN); >5 × ULN if associated with clinically suspected liver infiltration by mastocytosis or another disease for which the patient enrolled into the study
• Total bilirubin >1.5 × ULN; >3 × ULN if associated with liver infiltration by the disease being treated or in the presence of Gilbert's Disease (In the case of Gilbert's disease, a direct bilirubin > 2.0 ULN would be an exclusion.)
• Estimated (Cockroft-Gault formula) or measured creatinine clearance <40 mL/min
• Brain malignancy or metastases to the brain
• History of a seizure disorder or requirement for anti-seizure medication
• Known risk of intracranial bleeding, such as a brain aneurysm or history of subdural or subarachnoid bleeding
• Eosinophilia and known positivity for the FIP1L1-PGDFRA fusion, unless the patient has demonstrated relapse or progressive disease on prior imatinib therapy

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Avapritinib (also known as BLU-285); Avapritinib tablets for oral administration. Avapritinib will be dosed daily for 28 day cycles.	Drug: Avapritinib

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
Maximum tolerated dose (MTD) of avapritinib (also known as BLU-285)	During cycle 1 (28 days) of treatment
Number of patients with adverse and serious adverse events and changes in physical findings, vital signs, clinical laboratory results and ECG findings	Approximately 24 months
Recommended Phase 2 dose (RP2D) of avapritinib	Approximately 24 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Maximum plasma concentration of avapritinib	Blood samples may be taken at pre-dose, and 0.5, 1, 2, 4, 8 and 24 hrs post dose (plus 10 and 48 hrs post dose in Part 2) on Cycle 1 Day 1 and Cycle 1 Day 15, Pre-dose of Cycle 2 to 4, Day 1	Every cycle (28 days) up to cycle 4
Time to maximum plasma concentration of avapritinib	Blood samples may be taken at pre-dose, and 0.5, 1, 2, 4, 8 and 24 hrs post dose (plus 10 and 48 hrs post dose in Part 2) on Cycle 1 Day 1 and Cycle 1 Day 15, Pre-dose of Cycle 2 to 4, Day 1	Every cycle (28 days) up to cycle 4
Overall Response Rate	Including complete remission (CR), CR with partial recovery of peripheral blood (CRh), partial remission (PR) and clinical improvement (CI) using modified International Working Group Myeloproliferative Neoplasms Research and Treatment (IWG-MRT) and European competence network on mastocytosis (ECNM) criteria; and duration of response (DOR)	8, 24, 40, 68 and every 24 weeks until patient terminates from the study (approximately 24 months)
Morphologic response	Including morphologic complete remission (mCR), morphologic CR with partial recovery of peripheral blood (mCRh), and morphologic partial remission (mPR) based on Pure Pathologic Response	≥ 12 weeks
Changes in levels of serum tryptase and levels of V-kit Hardy-Zuckerman 4 feline sarcoma viral oncogene homolog (KIT) D816V allele burden in blood		Cycle (C)1Day (D)1, C1D15, C2D1, C3D1, C5D1, C7D1, C11D1, C18D1 every 6 cycles thereafter and at disease progression. (approximately 24 months)
Changes in patient reported symptoms and quality of life using the Patient Global Impression of Symptom Severity (PGIS) scale	Defined as change from Baseline	Part 2 only - Day 1 of Cycles 1-12
Changes in patient reported quality of life using the European Organization for Research and Treatment of Cancer Core Quality of Life Questionnaire (EORTC QLQ-C-30)	Defined as change from Baseline	Part 2 only - Day 1 of Cycles 1-12
Changes in patient reported outcomes using the advanced SM symptom assessment form (AdvSM-SAF)	Defined as change from Baseline	Part 2 only - daily from Day -7 through Cycle 12
Change in liver volume by imaging	mL	Day 1 of Cycles 5-18, and every 6 cycles thereafter (each cycle is 28 days)
Change in spleen volume by imaging	mL	Day 1 of Cycles 5-18, and every 6 cycles thereafter (each cycle is 28 days)

Collaborators and Investigators

• Sponsor: Blueprint Medicines Corporation

Publications and helpful links

General Publications

• Reiter A, Gotlib J, Alvarez-Twose I, Radia DH, Lubke J, Bobbili PJ, Wang A, Norregaard C, Dimitrijevic S, Sullivan E, Louie-Gao M, Schwaab J, Galinsky IA, Perkins C, Sperr WR, Sriskandarajah P, Chin A, Sendhil SR, Duh MS, Valent P, DeAngelo DJ. Efficacy of avapritinib versus best available therapy in the treatment of advanced systemic mastocytosis. Leukemia. 2022 Aug;36(8):2108-2120. doi: 10.1038/s41375-022-01615-z. Epub 2022 Jul 5.
• Reiter A, Schwaab J, DeAngelo DJ, Gotlib J, Deininger MW, Pettit KM, Alvarez-Twose I, Vannucchi AM, Panse J, Platzbecker U, Hermine O, Dybedal I, Lin HM, Rylova SN, Ehlert K, Dimitrijevic S, Radia DH. Efficacy and safety of avapritinib in previously treated patients with advanced systemic mastocytosis. Blood Adv. 2022 Nov 8;6(21):5750-5762. doi: 10.1182/bloodadvances.2022007539.
• DeAngelo DJ, Radia DH, George TI, Robinson WA, Quiery AT, Drummond MW, Bose P, Hexner EO, Winton EF, Horny HP, Tugnait M, Schmidt-Kittler O, Evans EK, Lin HM, Mar BG, Verstovsek S, Deininger MW, Gotlib J. Safety and efficacy of avapritinib in advanced systemic mastocytosis: the phase 1 EXPLORER trial. Nat Med. 2021 Dec;27(12):2183-2191. doi: 10.1038/s41591-021-01538-9. Epub 2021 Dec 6.

Study record dates

Study Major Dates

• Study Start (Actual): March 10, 2016
• Primary Completion (Actual): October 5, 2022
• Study Completion (Actual): January 19, 2023

Study Registration Dates

• First Submitted: September 15, 2015
• First Submitted That Met QC Criteria: September 25, 2015
• First Posted (Estimate): September 29, 2015

Study Record Updates

• Last Update Posted (Actual): March 17, 2023
• Last Update Submitted That Met QC Criteria: March 16, 2023
• Last Verified: March 1, 2023

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Skin Diseases; Immune System Diseases; Neoplasms, Connective and Soft Tissue; Neoplasms by Histologic Type; Hypersensitivity; Leukemia; Neoplasms, Connective Tissue; Immune Complex Diseases; Leukemia, Myeloid; Leukemia, Myeloid, Acute; Neoplasms; Mastocytosis; Mastocytosis, Systemic; Leukemia, Mast-Cell
• Other Study ID Numbers: BLU-285-2101; 2015-001661-12 (EudraCT Number)