The goal of this study is to determine the efficacy of the study drug olutasidenib to treat newly diagnosed pediatric and young adult patients with a high-grade glioma (HGG) harboring an IDH1 mutation.
The main question the study aims to answer is whether the combination of olutasidenib and temozolomide (TMZ) can prolong the life of patients diagnosed with an IDH-mutant HGG.
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.
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.
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.
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).
Parallel
Olutasidenib + TMZ
DrugOlutasidenib 150 mg PO BID + Temozolomide 200 mg/m2 PO QD
Establish the RP2D of Olutasidenib and Temozolomide (Feasibility cohort)
To identify the dose of olutasidenib that is feasible when given post-RT in combination with temozolomide as maintenance therapy in pediatric and young adult patients newly diagnosed with IDH1-mutant high-grade glioma
Assess Progression-Free Survival (PFS) in Grade 3 IDH1-mutant Astrocytoma (Stratum A)
To assess the post-RT efficacy of olutasidenib in newly diagnosed patients with WHO Grade 3 IDH1-mutant Astrocytoma treated with maintenance olutasidenib and temozolomide for 13 cycles followed by 13 cycles of single agent olutasidenib compared to molecularly-stratified and matched historical controls
Maximum plasma concentration [Cmax] of Olutasidenib
To characterize the plasma pharmacokinetic (PK) properties of olutasidenib in pediatric patients (e.g., 12 to \< 18 years of age), administered in combination with temozolomide (first year) and as single agent (second year) as maintenance chemotherapy by measuring the Maximum Concentration \[Cmax\] and Area Under the Curve (AUC) of olutasidenib in plasma (All strata).
Evaluate objective response rate (ORR) in HGG (All Strata)
Evaluate the radiographic objective response rate (ORR) defined as complete response (CR) + partial response (PR) in pediatric and young adult patients newly diagnosed with IDH1-mutant HGG treated with post-RT olutasidenib with temozolomide.
Evaluate Health-Related Quality of Life Outcomes (All Strata)
Evaluate health-related quality of life outcomes of pediatric and young adult patients newly-diagnosed with IDH1-mutant HGG treated with post-RT olutasidenib by patient and/or parent reporting at key timepoints in therapy using the patient reported outcomes measurement information system (PROMIS) survey. These survey systems report scores on a scale of 1(minimum) to 5 (maximum). The scores may reflect frequencies from "1-Never" to "5-Always" or levels of autonomy from "1-With no trouble" to "5-Not able to do". Scores are interpreted differently for the different outcome measures
Evaluate Overall Survival in IDH1-mutant Grade 3 Astrocytoma (Stratum A)
Determine distribution of OS in pediatric and young adult patients newly-diagnosed with IDH1-mutant Grade 3 Astrocytoma treated with post-RT olutasidenib and temozolomide for 13 cycles followed by 13 cycles of single agent olutasidenib compared to molecularly-stratified and matched historical controls.(Stratum A)
Assess Progression-Free Survival in IDH1-mutant Grade 4 Astrocytoma (Stratum B)
To assess the post-RT efficacy of olutasidenib in newly diagnosed patients with WHO Grade 4 IDH1-mutant Astrocytoma treated with maintenance olutasidenib and temozolomide for 13 cycles followed by 13 cycles of single agent olutasidenib compared to molecularly-stratified and matched historical controls
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Rigel Pharmaceuticals
Lead sponsor
Nationwide Children's Hospital
Collaborator
