NCT02561988

Brief Summary

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).

Trial Health

90
On Track

Trial Health Score

Automated assessment based on enrollment pace, timeline, and geographic reach

Enrollment
86

participants targeted

Target at P75+ for phase_1

Timeline
Completed

Started Mar 2016

Longer than P75 for phase_1

Geographic Reach
2 countries

11 active sites

Status
completed

Health score is calculated from publicly available data and should be used for screening purposes only.

Trial Relationships

Click on a node to explore related trials.

Study Timeline

Key milestones and dates

First Submitted

Initial submission to the registry

September 15, 2015

Completed
14 days until next milestone

First Posted

Study publicly available on registry

September 29, 2015

Completed
5 months until next milestone

Study Start

First participant enrolled

March 10, 2016

Completed
6.6 years until next milestone

Primary Completion

Last participant's last visit for primary outcome

October 5, 2022

Completed
4 months until next milestone

Study Completion

Last participant's last visit for all outcomes

January 19, 2023

Completed
Last Updated

March 17, 2023

Status Verified

March 1, 2023

Enrollment Period

6.6 years

First QC Date

September 15, 2015

Last Update Submit

March 16, 2023

Conditions

Aggressive Systemic MastocytosisSystemic Mastocytosis-associated Hematologic Non-mast Cell DiseaseMast Cell LeukemiaRelapsed or Refractory Myeloid Malignancies

Outcome Measures

Primary Outcomes (3)

  • 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 Outcomes (10)

  • Maximum plasma concentration of avapritinib

    Every cycle (28 days) up to cycle 4

  • Time to maximum plasma concentration of avapritinib

    Every cycle (28 days) up to cycle 4

  • Overall Response Rate

    8, 24, 40, 68 and every 24 weeks until patient terminates from the study (approximately 24 months)

  • Morphologic 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)

  • +5 more secondary outcomes

Study Arms (1)

Avapritinib (also known as BLU-285)

EXPERIMENTAL

Avapritinib tablets for oral administration. Avapritinib will be dosed daily for 28 day cycles.

Drug: Avapritinib

Interventions

AvapritinibDRUG
Avapritinib (also known as BLU-285)

Eligibility Criteria

Age18 Years+
Sexall
Healthy VolunteersNo
Age GroupsAdult (18-64), Older Adult (65+)

You may qualify if:

  • 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).
  • +3 more criteria

You may not qualify if:

  • 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
  • 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

Contact the study team to confirm eligibility.

Sponsors & Collaborators

Study Sites (11)

Stanford Cancer Institute

Stanford, California, 94305, United States

Location

University of Colorado Cancer Center

Denver, Colorado, 80045, United States

Location

Emory University

Atlanta, Georgia, 30322, United States

Location

Dana Farber Cancer Institute

Boston, Massachusetts, 02215, United States

Location

University of Michigan Health System

Ann Arbor, Michigan, 48109, United States

Location

Mount Sinai Hospital

New York, New York, 10029, United States

Location

University of Pennsylvania

Philadelphia, Pennsylvania, 19104, United States

Location

MD Anderson Cancer Center

Houston, Texas, 77030, United States

Location

Huntsman Cancer Institute

Salt Lake City, Utah, 84112, United States

Location

Beatson West of Scotland Cancer Centre

Glasgow, G12 0XL, United Kingdom

Location

Guy's Hospital

London, SE1 9RT, United Kingdom

Location

Related Publications (3)

  • 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.

    PMID: 35790816DERIVED

  • 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.

    PMID: 35640224DERIVED

  • 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.

    PMID: 34873347DERIVED

MeSH Terms

Conditions

Mastocytosis, SystemicLeukemia, Mast-CellRecurrence

Interventions

avapritinib

Condition Hierarchy (Ancestors)

MastocytosisNeoplasms, Connective TissueNeoplasms, Connective and Soft TissueNeoplasms by Histologic TypeNeoplasmsMast Cell Activation DisordersImmune System DiseasesLeukemiaLeukemia, Myeloid, AcuteLeukemia, MyeloidHematologic DiseasesHemic and Lymphatic DiseasesDisease AttributesPathologic ProcessesPathological Conditions, Signs and Symptoms

Study Design

Study Type
interventional
Phase
phase 1
Allocation
NA
Masking
NONE
Purpose
TREATMENT
Intervention Model
SINGLE GROUP
Sponsor Type
INDUSTRY
Responsible Party
SPONSOR

Study Record Dates

First Submitted

September 15, 2015

First Posted

September 29, 2015

Study Start

March 10, 2016

Primary Completion

October 5, 2022

Study Completion

January 19, 2023

Last Updated

March 17, 2023

Record last verified: 2023-03

Locations

US(9)GB(2)