Inclusion Criteria:
- - COHORT A and COHORT B: For the dose escalation phase, patients must be ≥ 12 months
and < 18 years of age at the time of study enrollment.
- - COHORT C and COHORT D: For the disease expansion phase, patients must be ≥ 12 months
and < 22 years of age at the time of study enrollment.
- - Patients with newly diagnosed primary high-grade glioma (HGG), diffuse midline
glioma (DMG) (excluding primary spinal tumors), or diffuse intrinsic pontine glioma
(DIPG) who are eligible to receive 54-59.4 grey (Gy) fractionated radiation at 1.8
Gy/day.
Patients must have had histologic verification of malignancy at original
diagnosis except in patients with DIPG as defined below.
- - COHORTS A AND C (SUPRATENTORIAL TUMORS):
- HGG and non-pontine DMG:
- Patients with newly diagnosed HGG (including diffuse hemispheric
glioma, H3 G34-mutant; diffuse pediatric-type high-grade glioma,
H3-wildtype and IDH-wildtype; astrocytoma; IDH-mutant; or
glioblastoma, IDH-wildtype): or non-pontine DMG (including diffuse
midline glioma, H3 K27-altered; diffuse pediatric-type high-grade
glioma, H3-wildtype and IDH-wildtype; astrocytoma; IDH-mutant; or
glioblastoma, IDH-wildtype) require histologic diagnosis.
- - COHORT B AND D (INFRATENTORIAL TUMORS):
- DIPG/pontine DMG or infratentorial HGG or DMG:
- Patients with newly diagnosed typical DIPG, defined as tumors with a
pontine epicenter and diffuse involvement of at least 2/3 of the pons
on at least 1 axial T2-weighted image, are eligible.
No histologic
confirmation is required.
- - Patients with infratentorial tumors that do not meet radiographic
criteria for typical DIPG (e.g., focal tumors or those involving less
than 2/3 of the pontine cross-sectional area with or without
extrapontine extension) are eligible if the tumors are biopsied and
proven to be high-grade gliomas (including diffuse midline glioma H3
K27-altered; diffuse pediatric-type high-grade glioma, H3-wildtype
and IDH-wildtype; astrocytoma; IDH-mutant; or glioblastoma,
IDH-wildtype) by institutional diagnosis.
- - Supratentorial tumors are defined as tumors with an epicenter in the
cerebral hemispheres, basal ganglia, thalamus, hypothalamus, or pituitary
gland.
- - Infratentorial tumors are defined as tumors with an epicenter in the
brainstem, cerebellum.
- - Patients with measurable or non-measurable (following a gross total resection)
disease.
- - Karnofsky ≥ 50% for patients > 16 year of age and Lansky ≥ 50% for patients ≤ 16
years of age.
- - Note: Patients who are unable to walk because of paralysis, but who are in a
wheelchair, will be considered ambulatory for the purpose of assessing the
performance score.
- - Prior therapy for any cancer diagnosis (including radiation) is not allowed with the
exception of surgery and/or corticosteroids.
If receiving corticosteroids, dose must
remain stable or decrease after enrollment.
- - Peripheral absolute neutrophil count (ANC) ≥ 1000/uL (must be performed within 7
days prior to enrollment unless otherwise indicated)
- Platelet count ≥ 100,000/uL (transfusion independent, defined as not receiving
platelet transfusions for at least 7 days prior to enrollment) (must be performed
within 7 days prior to enrollment unless otherwise indicated)
- Hemoglobin ≥ 8.0 g/dL at baseline (may receive red blood cell [RBC] transfusions)
(must be performed within 7 days prior to enrollment unless otherwise indicated)
- A creatinine based on age/sex as follows (must be performed within 7 days prior to
enrollment unless otherwise indicated):
- 1 to < 2 years: Maximum serum creatinine 0.6 mg/dL (male), 0.6 mg/dL (female)
- 2 to < 6 years: Maximum serum creatinine 0.8 mg/dL (male), 0.8 mg/dL (female)
- 6 to < 10 years: Maximum serum creatinine 1 mg/dL (male), 1 mg/dL (female)
- 10 to < 13 years: Maximum serum creatinine 1.2 mg/dL (male), 1.2 mg/dL (female)
- 13 to < 16 years: Maximum serum creatinine 1.5 mg/dL (male), 1.4 mg/dL (female)
- >= 16 years: Maximum serum creatinine 1.7 mg/dL (male),1.4 mg/dL (female) OR a
24 hour urine creatinine clearance ≥ 70 mL/min/1.73 m^2 OR a glomerular
filtration rate (GFR) ≥ 70 mL/min/1.73 m^2.
GFR must be performed using direct
measurement with a nuclear blood sampling method OR direct small molecule
clearance method (iothalamate or other molecule per institutional standard).
Note: Estimated GFR (eGFR) from serum creatinine, cystatin C or other estimates are not
acceptable for determining eligibility.
- - Note: The threshold creatinine values in this Table were derived from the Schwartz
formula for estimating GFR (Schwartz et al.
J. Peds, 106:522, 1985) utilizing child
length and stature data published by the CDC.
- - Bilirubin (sum of conjugated + unconjugated or total) ≤ 1.5 x upper limit of
normal (ULN) for age except in patients diagnosed with Gilbert's disease for
which bilirubin must be ≤ 3.0 × ULN (must be performed within 7 days prior to
enrollment unless otherwise indicated)
- Alanine aminotransferase (ALT) ≤ 3 x ULN, unless attributed to tumor
involvement then ALT ≤ 5 x ULN (must be performed within 7 days prior to
enrollment unless otherwise indicated)
- Aspartate aminotransferase (AST) ≤ 3 x ULN, unless attributed to tumor
involvement then AST ≤ 5 x ULN (must be performed within 7 days prior to
enrollment unless otherwise indicated)
- Albumin ≥ 2 g/dL (must be performed within 7 days prior to enrollment unless
otherwise indicated)
- No evidence of dyspnea at rest, no exercise intolerance and a pulse oximetry >
93%
- Patients with seizure disorder may be enrolled if on anticonvulsants and well
controlled as evidenced by no increase in seizure frequency in the prior 7
days.
If needed, evaluate use of enzyme-inducing anticonvulsants.
- - Serum lipase ≤ 1.5 ULN (must be performed within 7 days prior to enrollment
unless otherwise indicated)
- Prothrombin time (PT)/international normalization rate (INR) < 1.5 x ULN (must
be performed within 7 days prior to enrollment unless otherwise indicated)
- Patients must have the ability to swallow whole tablets (AZD1390 may not be
administered via nasogastric [NG]/gastric [G]-tubes)
Exclusion Criteria:
- Pregnant or breast-feeding women will not be entered on this study due to risks of
fetal and teratogenic adverse events as seen in animal/human studies, OR because
there is yet no available information regarding human fetal or teratogenic
toxicities.
Pregnancy tests must be obtained in girls who are post-menarchal. Males
or females of reproductive potential may not participate unless they have agreed to
use two effective methods of birth control, including a medically accepted barrier
or contraceptive method (eg, male or female condom) for the duration of the study.
Abstinence is an acceptable method of birth control. Women of childbearing potential
should use adequate contraception during study participation and for 6 months after
the last dose of AZD1390. Male patients with female partners of childbearing
potential should use adequate contraception during study participation and for 16
weeks after the last dose of AZD1390.
- - Investigational Drugs: Patients who are currently receiving another investigational
drug are not eligible.
- - Anti-cancer Agents: Patients who are currently receiving other anti-cancer agents
are not eligible with the exception of corticosteroids.
- - Anti-graft versus host disease (GVHD) agents post-transplant: Patients who are
receiving cyclosporine, tacrolimus or other agents to prevent graft-versus-host
disease post bone marrow transplant are not eligible for this trial.
- - CYP-450/Transport Proteins: Patients receiving any medications or substances that
are strong inhibitors or inducers of CYP3A4/5 enzyme are ineligible.
Moderate
inhibitors and inducers of CYP3A4/5 are permitted but caution should be exercised,
and patients monitored closely for possible drug interactions. Strong inhibitors or
inducers CYP3A4 should be stopped at least 2 weeks before the first dose of AZD1390
(3 weeks for St John's Wort). As part of the enrollment/informed consent procedures,
the patient will be counseled on the risk of interactions with other agents, and
what to do if new medications need to be prescribed or if the patient is considering
a new over-the-counter medicine or herbal product.
- - Enzyme-Inducing Anticonvulsants: Patients must not have received enzyme-inducing
anticonvulsants within 14 days prior to enrollment.
- - Patients who have an uncontrolled infection are not eligible.
- - Patients who have received a prior solid organ transplantation are not eligible.
- - Patients who in the opinion of the investigator may not be able to comply with the
safety monitoring requirements of the study are not eligible.
This includes patients
with rapidly declining neurological status.
- - Patients must have the ability to swallow whole tablets (AZD1390 may not be
administered via NG/G-tubes).
Patients with medical conditions that affect drug
absorption, such as short gut syndrome are not eligible.
- - Patients with known macular degeneration, uncontrolled glaucoma, or cataracts are
not eligible.
- - Patients with primary spinal cord high grade gliomas are not eligible.
- - Patients with metastatic disease are not eligible; Metastatic disease is defined as
distant intracranial or spinal metastasis including leptomeningeal disease, or tumor
cells within the CSF.
MRI of the spine with and without contrast must be performed
if metastatic disease is suspected by the treating physician.
- - Patients with gliomatosis type growth pattern (or diffuse spread) with involvement
of at least 3 lobes of the brain are not eligible with the exception of H3
K27M-mutant bithalamic tumors.
- - Patients with infant-type hemispheric high-grade gliomas are excluded.
- - Patients with BRAFV600E mutations are excluded.
- - Patients who are not able to receive protocol specified radiation therapy.
- - Patients with a history of radiotherapy as part of anti-cancer therapy are excluded.
- - Presence of myopathy or raised CK > 5 x ULN on 2 occasions at screening will result
in exclusion.
- - CK should not be measured following strenuous exercise or in the presence of a
plausible alternative cause of CK increase, which may confound interpretation
of the results.
- - If CK levels are significantly elevated at baseline (>5 x ULN) a confirmatory
test should be carried out within 5 - 7 days.
- - If the repeat test confirms a baseline CK >5 x ULN, treatment should not be
started.
- - HIV-infected patients on effective anti-retroviral therapy with undetectable viral
load within 6 months are eligible as long as they are NOT receiving anti-retroviral
agents that are strong inhibitors or inducers of CYP3A4 or substrates of UGT1A1 and
UGT1A9.
- - Evidence of clinically significant cardiac dysfunction or prolonged corrected QT
interval (QTc) (> 450 msec) on baseline electrocardiogram (EKG)
- Patients with known hepatitis B or C with detectable viral load.
- Any significant medical condition that in the medical judgement of the investigator
would compromise the patient's ability to tolerate study drug or participate in the
study
