| Eligibility |
Inclusion Criteria:
Age: Patients must be =12 months and = 21 years of age at the time of study enrollment.
Diagnosis: Patients with newly-diagnosed diffuse intrinsic pontine gliomas (DIPGs), defined
as tumors with a pontine epicenter and diffuse involvement of at least 2/3 of the pons, are
eligible without histologic confirmation.
Patients with brainstem tumors that do not meet radiographic criteria or are not considered
to be typical diffuse intrinsic pontine gliomas will be eligible if the tumors are biopsied
and proven to be high-grade gliomas (such as anaplastic astrocytoma, glioblastoma,
H3K27-mutant diffuse midline glioma) or diffuse astrocytoma.
Patients with newly-diagnosed non-brainstem high-grade glioma (HGG) are eligible.
Patients must have had histologically verified high-grade glioma such as anaplastic
astrocytoma, glioblastoma, H3 K27 mutant diffuse midline glioma etc.
Patients eligible for the surgical stratum include patients with:
1. Newly-diagnosed DIPG who are amenable to undergo biopsy at the recommendation of their
treating physician
2. Newly-diagnosed HGG for whom a second surgical resection is warranted for further
debulking or to achieve a near-total or gross total resection after initial diagnosis
has been made but prior to start of therapy.
Disease Status: Patients with disseminated DIPG or HGG are not eligible, and MRI of
spine must be performed if disseminated disease is suspected clinically by the
treating physician.
Performance Level: Karnofsky = 50 for patients > 16 years of age and Lansky = 50 for
patients = 16 years of age. Patients who are unable to walk because of paralysis, but
who are up in a wheelchair, will be considered ambulatory for the purpose of assessing
the performance score.
Neurologic Status: Patients must be able to swallow oral medications to be eligible
for study enrollment.
Patients enrolling on Part A (phase I, capsule formulation) must be able to swallow
whole capsules.
Prior Therapy: Patients must not have received any prior anticancer therapy. Prior
dexamethasone and/or surgery are permissible.
Organ Function Requirements:
Adequate Bone Marrow Function Defined as:
• Peripheral absolute neutrophil count (ANC) = 1000/mm3
• Platelet count = 100,000/mm3 (transfusion independent, defined as not receiving
platelet transfusions for at least 7 days prior to enrollment)
• Hemoglobin >8 g/dL (may be transfused).
Adequate Renal Function Defined as:
• Creatinine clearance or radioisotope GFR = 70ml/min/1.73 m2 or
• A serum creatinine based on age/gender as follows:
- 1 to < 2 years: 0.6 (Male) 0.6 (Female)
- 2 to < 6 years: 0.8 (Male) 0.8 (Female)
- 6 to < 10 years: 1 (Male) 1 (Female)
- 10 to < 13 years: 1.2 (Male) 1.2 (Female)
- 13 to < 16 years: 1.5 (Male) 1.4 (Female)
- 16 years: 1.7 (Male) 1.4 (Female)
Adequate Liver Function Defined as:
• Total bilirubin must be = 1.5 times institutional upper limit of normal for age
• AST(SGOT)/ALT(SGPT) < 3 times institutional upper limit of normal
• Serum albumin = 2g/dL
Adequate Cardiac Function Defined As:
- Ejection fraction of = 55% by echocardiogram.
- QTc = 480 msec.
Adequate Pulmonary Function Defined as
- No evidence of dyspnea at rest, and a pulse oximetry > 94% in room air if there is
clinical indication for determination
Adequate Neurologic Function Defined as:
- Patients with seizure disorder may be enrolled if on anticonvulsants and well
controlled.
Informed Consent: All patients and/or their parents or legally authorized
representatives must sign a written informed consent. Assent, when appropriate, will
be obtained according to institutional guidelines.
Exclusion Criteria:
Diagnosis: patients with a diagnosis of oligodendroglioma or oligoastrocytoma are not
eligible. Patients with juvenile pilocytic astrocytoma, are not eligible.
Patients with non-brainstem diffuse astrocytoma (grade 2) are not eligible for the HGG
stratum of the study.
Pregnancy or breast-feeding: Pregnant or breast-feeding women will not be entered on
this study due to known or unknown risks of fetal and teratogenic adverse events as
seen in animal/human studies. 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 an effective contraceptive method.
Patients of childbearing or child fathering potential must agree to use adequate
contraceptive methods (hormonal or barrier method of birth control; abstinence) while
being treated on this study and for 3 months after completing therapy. Note: The
definition of effective contraception will be based on the judgment of the principal
investigator or a designated associate.
Concomitant Medications
- Corticosteroids: Patients receiving corticosteroids are eligible. The use of
corticosteroids must be reported.
- 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.
- Anticonvulsants: Patients who are receiving enzyme inducing anticonvulsants as
listed in appendix II, are not eligible
- Patients who are receiving rifampin are not eligible.
- Patients who are receiving medications known to prolong QTc interval as listed in
appendix III are not eligible.
- Patients who are receiving duloxetine, alosetron or theophylline (CYP1A2
inhibitors) are not eligible
- Patients on beta-blockers are not eligible
- Selective serotonin reuptake inhibitors (SSRIs) such as citalopram (Celexa),
escitalopram (Lexapro), Fluoxetine (Prozac), fluvoxamine (Luvox), paroxetine
(Paxil), sertraline (Zoloft) should be used with caution but are not
contraindicated.
- Anticoagulants: patients who are receiving therapeutic anticoagulants including
warfarin, low-molecular weight heparin are not eligible
Nasogastric or G tube administration of PTC596 is not permissible.
Infection: Patients who have an uncontrolled infection 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.
Patients with evidence of bowel obstruction, malabsorption, or other contraindication
to oral medication are not eligible.
Patients with GI disease or other condition that could affect absorption or predispose
subject to gastrointestinal ulceration are not eligible.
Patients with an active peptic ulcer disease or inflammatory bowel disease (including
ulcerative colitis and Crohn's disease), diverticulitis, cholecystitis, symptomatic
cholangitis or appendicitis are not eligible.
Patients with serious non-healing wounds, ulcers, or bone fractures are not eligible.
Patients with moderate to severe pulmonary problems generally defined by need for
medical intervention (e.g., oxygen, medications) and/or limiting activities of daily
living (generally CTCAE Grade 2 or higher) or shortness of breath with limited
exertion are not eligible. Pulmonary conditions include (but are not limited to) COPD,
asthma, and hemi-pneumectomy.
Patients with malignancy related to HIV or solid organ transplant: known history of
HIV, HBV surface antigen positivity or positive HCV antibody are not eligible. Viral
testing is not required unless clinically indicated in patients without a known
history.
Patient with prior or ongoing clinically significant illness, medical or psychiatric
condition, medical history, physical findings, ECG findings, or laboratory abnormality
that, in the investigator's opinion, could affect the safety of the subject, or alter
the absorption, distribution, metabolism, or excretion of the study drugs, or could
impair the assessment of study results are not eligible.
Patients with any prior solid organ transplant are not eligible
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