| Eligibility |
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
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.
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 (ß-hCG) pregnancy test consistent with pregnancy obtained within 7 days
before the first dose of study drug. Patients with ß-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 ß-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.
|
