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A Drug-drug Interaction Study of Avapritinib and Midazolam

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.
ClinicalTrials.gov Identifier: NCT04908176
Recruitment Status : Recruiting
First Posted : June 1, 2021
Last Update Posted : March 13, 2023
Information provided by (Responsible Party):
Blueprint Medicines Corporation

Brief Summary:
The purpose of this study is to investigate the effect of multiple dosing of avapritinib on the pharmacokinetics (PK) of midazolam in adult patients with metastatic or unresectable gastrointestinal stromal tumors (GIST), recurrent gliomas, or other KIT mutant tumors.

Condition or disease Intervention/treatment Phase
Gastrointestinal Stromal Tumors GIST Non-resectable Advanced Solid Tumors Recurrent or Unresectable Central Nervous System (CNS) Tumors Drug: Avapritinib Drug: midazolam Phase 1

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 20 participants
Allocation: N/A
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Other
Official Title: A Drug-drug Interaction Study to Investigate the Effect of Avapritinib on the Pharmacokinetics of Midazolam in Patients With Unresectable or Metastatic Gastrointestinal Stromal Tumors (GIST) and Other Advanced Solid Tumors
Actual Study Start Date : August 24, 2022
Estimated Primary Completion Date : November 30, 2023
Estimated Study Completion Date : December 31, 2023

Arm Intervention/treatment
Experimental: Participants with metastatic, unresectable GIST, non-CNS solid tumors, or CNS tumors
Participants will receive 5 mg of midazolam orally on Day 1 and Day 17. Participants will receive avapritinib 300 mg daily, orally on starting on Day 3. Participants with CNS tumors will receive avapritinib 300 mg daily orally, until Day 56.
Drug: Avapritinib
avapritinib tablets
Other Name: BLU-285

Drug: midazolam
midazolam syrup

Primary Outcome Measures :
  1. maximum plasma concentration (Cmax) of midazolam [ Time Frame: Day 1 and Day 18 ]
  2. time of maximum plasma concentration (tmax) of midazolam [ Time Frame: Day 1 and Day 18 ]
  3. area under the plasma concentration-time curve (AUC) of midazolam [ Time Frame: Day 1 and Day 18 ]

Secondary Outcome Measures :
  1. Number of adverse events (AEs), serious AEs (SAEs), [ Time Frame: up to approximately 2 months ]
  2. Cmax at steady state (Cmax, ss) of avapritinib [ Time Frame: Day 18 ]
  3. Cmax at steady state (Cmax, ss) of metabolite [ Time Frame: Day 18 ]
  4. area under the plasma concentration-time curve at steady state (AUC,ss) of avapritinib [ Time Frame: Day 18 ]
  5. area under the plasma concentration-time curve at steady state (AUC,ss) of metabolite [ Time Frame: Day 18 ]

Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No

Inclusion Criteria:

  1. Must be ≥18 years of age at the time of signing the informed consent
  2. Confirmed diagnosis of

    • metastatic or unresectable KIT mutant GIST that has recurred or progressed after at least 4 lines of prior systemic SOC therapy or the Investigator has determined that treatment with SOC therapy is not appropriate for patients who failed at least 2 lines of prior SOC


    ---Non-resectable advance solid tumor with KIT mutation with progression following standard of care treatment.


    ---Confirmed diagnosis of recurrent or unresectable CNS tumors including :IDH-mutant astrocytoma, IDH-mutant oligodendroglioma, glioblastoma, H3K27-altered diffuse midline glioma, H3G34-mutant diffuse hemispheric glioma, midline glioma (with unknown H3K27 mutation status) that has failed prior radiation or systemic SOC therapy.

  3. Must be able to swallow an oral medication
  4. Must have Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 2
  5. Patient agrees to use contraception consistent with local regulations
  6. Must provide signed informed consent to participate in the study

Exclusion Criteria:

  1. Patients with GIST that harbors a known PDGFRA mutation
  2. Known hypersensitivity to avapritinib, midazolam, or any of their excipients
  3. Have received previous therapy with avapritinib
  4. Have any of the following laboratory abnormalities before the first dose of study drug:

    • Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) >3 × upper limit of normal (ULN) if no hepatic metastases are present; >5 × ULN if hepatic metastases are present
    • Total bilirubin >1.5 × ULN; >3 × ULN in the presence of Gilbert's Disease
    • Estimated (Cockcroft-Gault formula) or measured creatinine clearance <60 mL/min
    • Platelet count <100 × 10^9/liter (L)
    • Absolute neutrophil count (ANC) <1.0 × 10^9/L
    • Hemoglobin <9 grams per deciliter (g/dL). Transfusion and erythropoietin may be used to reach at least 9 g/dL but must have been administered at least 2 weeks before the first dose of the study drug.
  5. Require therapy with a concomitant medication that is a strong and moderate CYP3A4 inhibitors or inducers
  6. Consumption of any nutrients known to modulate CYP3A4 enzymes activity (eg, grapefruit or grapefruit juice, pomelo juice, star fruit, or Seville [blood] orange and derivative products, cruciferous vegetables [eg, broccoli, cauliflower, cabbage, brussel sprouts]) within 14 days before screening and during the study until the end of the Main Treatment Period
  7. Have received a prior anticancer drug less than 5 half-lives or 14 days (whichever is shorter) before screening
  8. Have had a major surgical procedure within 14 days of the first dose of study drug or have significant traumatic injury within 28 days before screening
  9. Have history of a cerebrovascular accident or transient ischemic attacks within 1 year before screening
  10. Have known risk of intracranial bleeding, such as a brain aneurysm or history of subdural or subarachnoid bleeding
  11. Have corrected QT interval using Fridericia's formula (QTcF) >450 msec
  12. Have clinically significant, uncontrolled, cardiovascular disease, including congestive heart failure Grades 2, 3, or 4 according to the New York Heart Association classification, myocardial infarction, or unstable angina within the previous 6 months, or uncontrolled hypertension
  13. Have experienced any hemorrhage or bleeding event National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) Version 5.0 Grade ≥3 within 4 weeks before screening. Exceptions are patients with primary CNS tumors who are eligible if the Grade ≥3 bleeding event was in the CNS and it occurred 2 weeks or more prior to the first dose of avapritinib.
  14. Patients who have a symptomatic nonhealing wound, ulcer, GI perforation, or bone fracture
  15. Have received organ or allogenic bone marrow or peripheral blood stem cell transplant
  16. Have known diagnosis of human immunodeficiency virus infection or active viral hepatitis; viral testing is not required
  17. History of alcohol consumption exceeding 2 standard drinks per day on average (1 standard drink = 14 grams of alcohol). Alcohol consumption will be prohibited 48 hours before screening and throughout the entire the Main Treatment Period
  18. Use of tobacco- or nicotine-containing products within 3 months of enrollment
  19. Is a female patient who is unwilling, if not postmenopausal or surgically sterile, to abstain from sexual intercourse or employ highly effective contraception from the time of informed consent and for until at least 6 weeks after the last dose of study drug. Males who are unwilling, if not surgically sterile, to abstain from sexual intercourse or employ highly effective contraception from the time of informed consent and for at least 6 weeks after the last dose of study drug.
  20. Is a female patient who is pregnant, as documented by a serum beta human chorionic gonadotropin (β-hCG) pregnancy test consistent with pregnancy obtained within 7 days before the first dose of study drug. Patients with β-hCG values that are within the range for pregnancy but are not pregnant (false positives) may be enrolled with written consent of the Sponsor after pregnancy has been ruled out. Females of nonchildbearing potential (postmenopausal for more than 12 months, bilateral tubal ligation, bilateral oophorectomy, or hysterectomy) do not require a serum β-hCG test.
  21. Female who is breastfeeding
  22. Have a prior or ongoing clinically significant illness, medical condition, surgical history, physical finding, or laboratory abnormality that, in the Investigator's opinion, could affect the safety of the patient, alter the absorption, distribution, metabolism or excretion of the study drugs, or impair the assessment of study results.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04908176

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Contact: Blueprint Medicines 617-714-6707 medinfo@blueprintmedicines.com

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United States, Florida
Mayo Clinic Florida Recruiting
Jacksonville, Florida, United States, 32224
Principal Investigator: Steven Attia, D.O.         
United States, Michigan
University of Michigan Recruiting
Ann Arbor, Michigan, United States, 48103
Principal Investigator: Denise Leung, MD         
United States, Pennsylvania
Thomas Jefferson University, Sidney Kimmel Cancer Center Recruiting
Philadelphia, Pennsylvania, United States, 19107
Principal Investigator: Iyad Alnahhas, MD         
Sponsors and Collaborators
Blueprint Medicines Corporation
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Responsible Party: Blueprint Medicines Corporation
ClinicalTrials.gov Identifier: NCT04908176    
Other Study ID Numbers: BLU-285-1107
First Posted: June 1, 2021    Key Record Dates
Last Update Posted: March 13, 2023
Last Verified: March 2023
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by Blueprint Medicines Corporation:
IDH-mutant astrocytoma
IDH-mutant oligodendroglioma
H3K27-altered diffuse midline glioma
H3G34-mutant diffuse hemispheric glioma
midline glioma
Additional relevant MeSH terms:
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Gastrointestinal Stromal Tumors
Neoplasms, Connective Tissue
Neoplasms, Connective and Soft Tissue
Neoplasms by Histologic Type
Gastrointestinal Neoplasms
Digestive System Neoplasms
Digestive System Diseases
Gastrointestinal Diseases
Adjuvants, Anesthesia
Hypnotics and Sedatives
Central Nervous System Depressants
Physiological Effects of Drugs
Anti-Anxiety Agents
Tranquilizing Agents
Psychotropic Drugs
Anesthetics, Intravenous
Anesthetics, General
GABA Modulators
GABA Agents
Neurotransmitter Agents
Molecular Mechanisms of Pharmacological Action