Criteria TarGeT-D study strata definitions.
- - Stratum A: Patients with localized, intracranial, non-pontine, and non-thalamic IDH 1
mutant Astrocytoma, CNS WHO Grade 3.
- - Stratum B: Patients with localized, intracranial, non-pontine, and non-thalamic IDH 1
mutant Astrocytoma, CNS WHO Grade 4.
- - Stratum C: Patients with IDH-1 mutant DIPG, primary thalamic and spinal cord IDH-1
mutant HGG.
Inclusion Criteria:
1. Inclusion criteria already met to enroll on TarGeT-SCR (central molecular and
histopathologic screening) based on:
1.1) Age: patients must be ≥12 years and ≤39 years of age at the time of enrollment on
TarGeT-SCR. 1.2) Diagnosis:
- - Patients with a newly-diagnosed IDH1-mutant HGG including DIPG are eligible.
All
patients must have tumor tissue from diagnostic biopsy or resection, without
exceptions. The diagnosis of HGG, including DIPG, must have been confirmed
through TarGeT-SCR.
- - For the diagnosis of DIPG, patients must have a tumor with pontine epicenter and
diffuse involvement of at least 2/3 of the pons, and histopathology consistent
with diffuse WHO Grade 2-4 glioma.
- - All other HGG must be WHO Grade 3 or 4.
1.3) Disease status: There are no disease status requirements for enrollment.
- - Measurable disease is not required.
Patients without measurable disease are
eligible.
- - Primary spinal tumor: Patients with a primary spinal HGG are eligible.
- - Patient must not have metastatic disease.
2. Inclusion criteria for assignment to TarGeT-D, for all strata:
2.1 Presence of at Least One Relevant Actionable Somatic Mutation in IDH1 Gene, Detailed
Here:
- - R132H, R132C, R132S, R132G or R132L.
- - Patients whose tumors harbor other alterations in addition to IDH1 mutation will
potentially be eligible following consensus recommendation by the international
multidisciplinary molecular screening committee.
- - Patients with IDH2 mutations are not eligible.
- - Patients with oligodendroglioma, IDH-mutant and 1p/19q-codeleted are not eligible.
2.2 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.
2.3 Prior Therapy. 2.3.1 Surgery, radiation, and/or dexamethasone are permissible. Temozolomide administered
concurrently with radiotherapy is permissible. No other prior anticancer therapy for HGG
will be allowed.
2.3.2 Radiation therapy requirements: RT, delivered via photon or proton beam, must have
been administered at a standard dose including 54 Gy in 30 fractions for DIPG, 59.4 Gy in
33 fractions or 54-60 Gy in 30 fractions for other HGG or 45-50.4 Gy for primary spinal
disease. Any variances in the radiotherapy dose within 10% of the standard doses outlined
above will be discussed with the Study Chair to confirm eligibility prior to study
enrollment.
2.3.3 Timing between diagnosis and start of RT: Patients must have started RT within 31
calendar days of initial diagnosis defined as the date of diagnostic biopsy or resection;
if a patient underwent two upfront surgeries (e.g., biopsy then resection or debulking),
this is the date of the second surgery.
2.3.4 Timing post-RT.
- - Patients in pre-maintenance phase must enroll and start treatment no later than 21
calendar days post-completion of RT.
- - Patients not in pre-maintenance phase must enroll and start treatment no later than 35
calendar days post-completion of RT.
2.4 Organ Function Requirements. 2.4.1 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).
2.4.2 Adequate Renal Function Defined as.
- - Creatinine clearance or radioisotope GFR ≥ 70ml/min/1.73 m2 OR.
- - Maximum serum creatinine based on age/gender as follows: 10 to < 13 yrs=1.2 mg/dL for
males and females.
13 to < 16 yrs=1.5 mg/dL for males and 1.4 mg/dL for females.
2.4.3 Adequate Liver Function Defined as:
- - Total bilirubin must be ≤ 1.5 × institutional ULN.
- - AST(SGOT)/ALT(SGPT) < 3 × institutional ULN.
- - Alkaline Phosphatase < 3 × institutional ULN.
2.4.4 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:
1. Pregnancy or Breast-Feeding: Pregnant or breast-feeding women will not be entered on
this study due to unknown potential risks of fetal and teratogenic adverse events as
seen in animal studies. Pregnancy tests must be obtained in girls who are
post-menarchal. Patients of childbearing or child fathering potential must agree to
use one highly effective method of contraception while being treated on this study and
for 3 months after completing therapy. A woman is considered of childbearing potential
if she is fertile, following menarche and until becoming post-menopausal unless
permanently sterile. A postmenopausal state is defined as no menses for 12 months
without an alternative medical cause. A high follicle stimulating hormone (FSH) level
in the postmenopausal range may be used to confirm a post-menopausal state in women
not using hormonal contraception or hormonal replacement therapy. However, in the
absence of 12 months of amenorrhea, a single FSH measurement is insufficient. A man is
considered fertile after puberty unless permanently sterile by bilateral orchidectomy.
Male participants should refrain from sperm donation throughout the duration of
treatment and for 3 months after completion of therapy.
A highly effective contraception method is defined as one that results in a low
failure rate (<1% per year) when used consistently and correctly. The following are
considered highly effective contraception methods:
- - Combined estrogen and progesterone containing hormonal contraception associated
with inhibition of ovulation.
- - Progesterone-only hormonal contraception associated with inhibition of ovulation.
- - Intra Uterine Device (IUD).
- - Intra uterine hormone releasing system.
- - Bilateral tubal occlusion.
- - Sexual abstinence (avoiding heterosexual intercourse).
- - The following contraceptive measures are NOT considered effective:
- Progesterone-only hormonal contraception (birth control pill) that that does
NOT stop ovulation.
- - Male or female condom with or without spermicide.
- - Cap, diaphragm, or sponge with spermicide.
2. Using the following types of 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: Concurrent anti-cancer agents are not allowed with the
exception of temozolomide given concurrently with RT and as post RT maintenance
therapy.
- - Anticonvulsants: Patients who are receiving enzyme inducing anticonvulsants that
are strong inducers of CYP3A4/5 are not eligible.
- - Strong CYP3A4/5 inducers: Patients who are receiving strong inducers of CYP3A4/5
are not eligible.
Strong inducers of CYP3A4/5 should be avoided from 14 days
prior to or 5 half-lives (whichever is longer) enrollment to the end of the
study.
- - Patients who are receiving medications known to prolong QTc interval 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 anticoagulation with
warfarin are not eligible.
3. Other Criteria.
- - 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 known clinically significant active malabsorption syndrome or other
condition that could affect absorption are not eligible.
- - 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.
- - Patients with prior or ongoing clinically significant illness, medical or
psychiatric condition, that, in the investigator's opinion, could affect the
safety of the subject, or could impair the assessment of study results are not
eligible.
- - Patients with any prior solid organ transplant are not eligible.
- - Patients with secondary/radiation-related HGG are not eligible.
- - Patients with metastatic/disseminated HGG who have received CSI are not eligible.
