|
|
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 |
|
|
|
|
|
OR |
|
|
|
|
|
--Non-resectable advance solid tumor with KIT mutation with progression following |
|
|
|
|
|
standard of care treatment |
|
|
|
|
|
OR |
|
|
|
|
|
--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 |
|
|
|
|
|
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
|
|
|
|
|
|
Have known risk of intracranial bleeding, such as a brain aneurysm or history of
|
|
|
|
|
|
subdural or subarachnoid bleeding
|
|
|
|
|
|
Have corrected QT interval using Fridericia's formula (QTcF) >450 msec
|
|
|
|
|
|
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
|
|
|
|
|
|
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
|
|
|
|
|
|
Patients who have a symptomatic nonhealing wound, ulcer, GI perforation, or bone
|
|
|
|
|
|
fracture
|
|
|
|
|
|
Have received organ or allogenic bone marrow or peripheral blood stem cell transplant
|
|
|
|
|
|
Have known diagnosis of human immunodeficiency virus infection or active viral
|
|
|
|
|
|
hepatitis; viral testing is not required
|
|
|
|
|
|
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
|
|
|
|
|
|
Use of tobacco- or nicotine-containing products within 3 months of enrollment
|
|
|
|
|
|
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
|
|
|
|
|
|
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
|
|
|
|
|
|
Female who is breastfeeding
|
|
|
|
|
|
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
|
|
|
|