A Drug-drug Interaction Study of Avapritinib and Midazolam

NCT04908176 | Completed Phase 1 FDA Drug

• 1 other identifier: BLU-285-1107
• Study Type: interventional
• Target: 10
• Locations: 1 country
• Sites: 3

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.

Conditions

Gastrointestinal Stromal Tumors; GIST; Non-resectable Advanced Solid Tumors; Recurrent or Unresectable Central Nervous System (CNS) Tumors

Keywords

Avapritinib; Midazolam; GIST; BLU-285; KIT; IDH-mutant astrocytoma; IDH-mutant oligodendroglioma; glioblastoma; H3K27-altered diffuse midline glioma; H3G34-mutant diffuse hemispheric glioma; midline glioma

Outcome Measures

Primary Outcomes (3)

• maximum plasma concentration (Cmax) of midazolam

  Day 1 and Day 18

• time of maximum plasma concentration (tmax) of midazolam

  Day 1 and Day 18

• area under the plasma concentration-time curve (AUC) of midazolam

  Day 1 and Day 18

Secondary Outcomes (5)

• Number of adverse events (AEs), serious AEs (SAEs),

  up to approximately 2 months

• Cmax at steady state (Cmax, ss) of avapritinib

  Day 18

• Cmax at steady state (Cmax, ss) of metabolite

  Day 18

• area under the plasma concentration-time curve at steady state (AUC,ss) of avapritinib

  Day 18

• area under the plasma concentration-time curve at steady state (AUC,ss) of metabolite

  Day 18

Study Arms (1)

Participants with metastatic, unresectable GIST, non-CNS solid tumors, or CNS tumors

EXPERIMENTAL

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; Drug: midazolam

Interventions

Avapritinib DRUG

avapritinib tablets

Also known as: BLU-285

Participants with metastatic, unresectable GIST, non-CNS solid tumors, or CNS tumors

midazolam DRUG

midazolam syrup

Participants with metastatic, unresectable GIST, non-CNS solid tumors, or CNS tumors

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Must be ≥18 years of age at the time of signing the informed consent
• 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.
• Must be able to swallow an oral medication
• Must have Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 2
• Patient agrees to use contraception consistent with local regulations
• Must provide signed informed consent to participate in the study

You may not qualify if:

• Patients with GIST that harbors a known PDGFRA mutation
• Known hypersensitivity to avapritinib, midazolam, or any of their excipients
• Have received previous therapy with avapritinib
• 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.
• Require therapy with a concomitant medication that is a strong and moderate CYP3A4 inhibitors or inducers
• 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
• Have received a prior anticancer drug less than 5 half-lives or 14 days (whichever is shorter) before screening
• 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
• Have history of a cerebrovascular accident or transient ischemic attacks within 1 year before screening

Sponsors & Collaborators

• Blueprint Medicines Corporation: lead

Study Sites (3)

Mayo Clinic Florida

Jacksonville, Florida, 32224, United States

Location

University of Michigan

Ann Arbor, Michigan, 48103, United States

Location

Thomas Jefferson University, Sidney Kimmel Cancer Center

Philadelphia, Pennsylvania, 19107, United States

Location

MeSH Terms

Conditions

Gastrointestinal Stromal Tumors; Recurrence; Neoplasms; Glioblastoma

Interventions

avapritinib; Midazolam

Condition Hierarchy (Ancestors)

Neoplasms, Connective Tissue; Neoplasms, Connective and Soft Tissue; Neoplasms by Histologic Type; Gastrointestinal Neoplasms; Digestive System Neoplasms; Digestive System Diseases; Gastrointestinal Diseases; Disease Attributes; Pathologic Processes; Pathological Conditions, Signs and Symptoms; Astrocytoma; Glioma; Neoplasms, Neuroepithelial; Neuroectodermal Tumors; Neoplasms, Germ Cell and Embryonal; Neoplasms, Glandular and Epithelial; Neoplasms, Nerve Tissue

Intervention Hierarchy (Ancestors)

Benzodiazepines; Benzazepines; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Heterocyclic Compounds

Study Design

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

Study Record Dates

• First Submitted: May 27, 2021
• First Posted: June 1, 2021
• Study Start: August 24, 2022
• Primary Completion: March 1, 2024
• Study Completion: May 10, 2024
• Last Updated: December 13, 2024

Record last verified: 2024-12

Data Sharing

• IPD Sharing: Will not share

Locations

US (3)