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.
