Inclusion Criteria. 1. Participant must be 2 to < 18 years of age at the time of signing the informed
consent.
2. Diagnosis. 1. Participant has confirmed diagnosis of R/R solid tumor, including CNS tumors,
with a mutation (including non-synonymous point mutations, insertions, and
deletions) in PDGFRA and/or KIT (confirmed by local mutational testing of tumor
sample) that has progressed despite standard therapy and no alternative
treatment option is available. Participant with R/R solid tumors with only
PDGFRA and/or KIT amplifications may be included with approval from the
Sponsor.
OR. 2. Participant has confirmed diagnosis of DMG-H3K27a (confirmed by local testing
of tumor sample) that has failed standard therapy or for which no standard
therapy that may convey clinical benefit exists, as judged by the investigator.
3. Participants with CNS disease should be on a stable (≤ 10% change) or decreasing
dose of corticosteroids for at least 7 days prior to first dose of avapritinib, with
no plans for dose escalation.
4. Disease extent: a. Part 1: All participants must have at least 1 measurable lesion
as defined by RECIST v1.1 or Response Assessment in Neuro-Oncology (RANO) (for CNS
tumors). If radiation therapy has been administered, at least 1 measurable lesion
must not have been irradiated, or must have clearly progressed since being
irradiated as per RANO and must be ≥ 12 weeks from radiation to any target lesion.
b. Part 2: All participants must have at least 1 measurable lesion as defined by
RECIST v1.1 or RANO (for CNS tumors). For Participants with DMG-H3K27a or PDGFRA
and/or KIT mutant/amplified solid tumors, including CNS tumors that have progressed
despite prior therapy, who have received radiation therapy, at least 1 measurable
lesion must not have been irradiated, or must have clearly progressed since being
irradiated as per RANO and must be ≥ 12 weeks from radiation to any target lesion.
For up to 5 Participants with newly diagnosed DMG-H3K27a where there is no standard
therapy that may convey clinical benefit exists as judged by the investigator,
progression of disease of a measurable lesion after irradiation is not required.
5. A Lansky (< 16 years of age) or Karnofsky (≥ 16 years of age) score of at least 50.
If the Participant is unable to walk due to paralysis, but is mobile in a
wheelchair, the participant is considered ambulatory for the purpose of assessing
their performance status.
6. Participant agrees to utilize contraception consistent with local regulations.
- - Male participants: Are vasectomized, or agree to use condoms, as defined in
Section 5.4.
2, from the start of Screening until 6 weeks after the last dose of
study treatment, or practice true abstinence (when this is in line with the
preferred and usual lifestyle of the Participant, see Section 5.4.2), or have a
female partner who is NOT of childbearing potential.
- - Female participants: Agree to use effective contraception, as defined in
Section 5.4.
2, from the start of Screening until 6 weeks after the last dose of
study treatment and have a male partner who uses a condom, or practice true
abstinence (when this is in line with the preferred and usual lifestyle of the
Participant), or have a male partner who is vasectomized with confirmed
azoospermia.
7. Participant can give written informed consent/assent before any study-specific
Screening procedures (if feasible). Parental/legal guardian consent will be
determined by local, regional, and/or national guidelines.
Exclusion Criteria. 1. Participant has any of the following within 14 days before the first dose of study
treatment:
1. Platelet count < 75 × 10^9/L (< 100 × 10^9/L if a CNS tumor) with no platelet
transfusion within 14 days prior to the measurement.
2. Absolute neutrophil count (ANC) < 1.0 × 10^9/L.
3. Hemoglobin < 8.0 g/dL with no RBC transfusion ≤ 7 days prior to the
measurement.
4. AST or ALT > 3 × the ULN for age; except in Participants with tumor involvement
of the liver who must not have AST and ALT > 5 × ULN for age.
5. Total bilirubin > 1.5 × ULN for age; and in presence of Gilbert's syndrome,
total bilirubin > 3 × ULN or direct bilirubin > 1.5 × ULN.
6. Serum creatinine > 1.5 × ULN for age.
7. International normalized ratio or prothrombin time (PT) > ULN (> 1.5 × ULN if
on prophylactic reversible anticoagulants).
2. Participant has a QTcF > 470 msec. Participant has a familial or personal history of
prolonged QT syndrome or Torsades de pointes.
3. Participant has clinically significant, uncontrolled cardiovascular disease
including congestive heart failure Grade III or IV according to the New York Heart
Association classification; myocardial infarction or unstable angina within the
previous 6 months, uncontrolled hypertension (> 95th percentile for age), or
clinically significant, uncontrolled arrhythmias, including bradyarrhythmias that
may cause QT prolongation (eg, Type II second-degree heart block or third-degree
heart block).
4. Participant received the following systemic antineoplastic therapies:
1. Temozolomide within 4 weeks prior to the first dose of study drug. 2. Nitrosurea within 6 weeks prior to the first dose of study drug. 3. Any other systemic antineoplastic therapy (including experimental therapy)
within 5 half-lives or 28 days prior to the first dose of study drug, whichever
is shorter.
4. Focal external beam radiotherapy, including stereotactic radiosurgery, within 6
weeks prior to the first dose of avapritinib to either target or nontarget
lesions. Systemic radiopharmaceuticals, including nonstereotactic radiosurgery,
within 2 weeks of the first dose of avapritinib (within 6 weeks for
Participants with CNS tumors). Craniospinal irradiation within 6 weeks prior to
the first dose of avapritinib.
5. All AEs related to other antineoplastic therapies (eg, systemic
antineoplastics, radiotherapy) must have resolved to Grade ≤ 1 (Grade ≤ 2 for
peripheral neuropathy and/or ototoxicity) prior to the first dose of
avapritinib.
5. Participant has previously received treatment with avapritinib.
6. Participant received autologous stem cell transplant following myeloablative therapy
or chimeric antigen receptor T cell therapy within 3 months prior to the first dose
of avapritinib or prior allogeneic stem cell transplant within 1 year and no
evidence of Grade 1 or greater graft-versus-host disease and no immunosuppressants
for graft-versus-host disease (steroids for primary malignancy being permitted).
Participants who received stem cell reinfusion following nonmyeloablative therapy
are eligible once they meet the peripheral blood count criteria in Exclusion
Criterion #1.
7. Participant requires ongoing treatment or has received treatment within 28 days
before the start of avapritinib administration with drugs or foods that are strong
CYP3A inhibitors or inducers.
8. Participant has had a major surgical procedure within 14 days of the first dose of
study treatment (procedures such as central venous catheter placement, tumor needle
biopsy, and feeding tube placement are not considered major surgical procedures).
9. Participant has a history of another primary malignancy that has been diagnosed or
required therapy within 3 years before the first dose of avapritinib. The following
prior malignancies are not exclusionary: completely resected basal cell and squamous
cell skin cancer, curatively treated localized prostate cancer, and completely
resected carcinoma in situ of any site.
10. Female subjects of childbearing potential who are 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 at least 6 weeks after the
last dose of study treatment. Male subjects 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 treatment.
11. Participant is pregnant, as documented by a serum β-hCG pregnancy test consistent
with pregnancy obtained at Screening and within 72 hours before the first dose of
study treatment. Participants 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. Female subjects of
nonchildbearing potential (premenarchal, bilateral tubal ligation, bilateral
oophorectomy, or hysterectomy) do not require a serum β-hCG test.
12. Participant is breastfeeding.
13. Participant has 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 Participant; alter the
absorption, distribution, metabolism, or excretion of the study drug; or impair the
assessment of study results.
14. History of thrombosis requiring treatment within the past 6 months. This exclusion
does not apply to catheter-related thrombosis if the catheter has been removed and
did not require any other treatment in the previous 3 months.
15. Participants who require anticoagulants, with the exception of stable doses of
prophylactic reversible anticoagulants.
16. Participants who are unable to swallow tablets (in Part 1) or minitablets (in Part
2) within the sprinkle capsules.
17. Participants with a known risk of intracranial bleeding, such as a brain aneurysm
that has not been removed or repaired, or a history of intracranial bleeding within
the past year, or radiographic evidence of hemorrhage on Screening MRI. Exceptions
are: Participants with primary CNS tumors (provided they have not had CNS bleeding
within 2 weeks of the first dose of avapritinib) or Participants with punctate
hemorrhages < 3 mm.
18. History of a seizure disorder that is not well controlled on current antiepileptic
medications.
19. Participant is unwilling or unable to comply with scheduled visits, treatment
administration plan, laboratory tests, or other study procedures and study
restrictions.
