Study of Olutasidenib and Temozolomide in HGG

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-1mutant HGG.

Inclusion Criteria:

1. Inclusion criteria already met to enroll on TarGeT-SCR (central molecular andhistopathologic screening) based on:

1.1) Age: patients must be ≥12 years and ≤39 years of age at the time of enrollmenton 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 beenconfirmed through TarGeT-SCR.

• For the diagnosis of DIPG, patients must have a tumor with pontine epicenterand diffuse involvement of at least 2/3 of the pons, and histopathologyconsistent 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 areeligible.

• 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 willpotentially be eligible following consensus recommendation by the internationalmultidisciplinary 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 21calendar 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 receivingplatelet 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/dLfor 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 patientsand/or their parents or legally authorized representatives must sign a writteninformed consent. Assent, when appropriate, will be obtained according toinstitutional guidelines.

Exclusion Criteria:

1. Pregnancy or Breast-Feeding: Pregnant or breast-feeding women will not be entered onthis study due to unknown potential risks of fetal and teratogenic adverse events asseen in animal studies. Pregnancy tests must be obtained in girls who arepost-menarchal. Patients of childbearing or child fathering potential must agree touse one highly effective method of contraception while being treated on this studyand for 3 months after completing therapy. A woman is considered of childbearingpotential if she is fertile, following menarche and until becoming post-menopausalunless permanently sterile. A postmenopausal state is defined as no menses for 12months without an alternative medical cause. A high follicle stimulating hormone (FSH) level in the postmenopausal range may be used to confirm a post-menopausalstate in women not using hormonal contraception or hormonal replacement therapy.However, in the absence of 12 months of amenorrhea, a single FSH measurement isinsufficient. A man is considered fertile after puberty unless permanently sterileby bilateral orchidectomy. Male participants should refrain from sperm donationthroughout 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 lowfailure rate (<1% per year) when used consistently and correctly. The following areconsidered highly effective contraception methods:

• Combined estrogen and progesterone containing hormonal contraception associatedwith inhibition of ovulation.

• Progesterone-only hormonal contraception associated with inhibition ofovulation.

• Intra Uterine Device (IUD).

• Intra uterine hormone releasing system.

• Bilateral tubal occlusion.

• Vasectomized partner.

• Sexual abstinence (avoiding heterosexual intercourse).

• The following contraceptive measures are NOT considered effective:

• Progesterone-only hormonal contraception (birth control pill) that thatdoes 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 ofcorticosteroids must be reported.

• Investigational Drugs: Patients who are currently receiving anotherinvestigational drug are not eligible.

• Anti-cancer Agents: Concurrent anti-cancer agents are not allowed with theexception of temozolomide given concurrently with RT and as post RT maintenancetherapy.

• Anticonvulsants: Patients who are receiving enzyme inducing anticonvulsantsthat are strong inducers of CYP3A4/5 are not eligible.

• Strong CYP3A4/5 inducers: Patients who are receiving strong inducers ofCYP3A4/5 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 ofthe study.

• Patients who are receiving medications known to prolong QTc interval are noteligible

• 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 notcontraindicated.

• Anticoagulants: patients who are receiving therapeutic anticoagulation withwarfarin 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 complywith the safety monitoring requirements of the study are not eligible.

• Patients with known clinically significant active malabsorption syndrome orother condition that could affect absorption are not eligible.

• Patients with malignancy related to HIV or solid organ transplant: knownhistory of HIV, HBV surface antigen positivity or positive HCV antibody are noteligible. Viral testing is not required unless clinically indicated in patientswithout a known history.

• Patients with prior or ongoing clinically significant illness, medical orpsychiatric condition, that, in the investigator's opinion, could affect thesafety of the subject, or could impair the assessment of study results are noteligible.

• 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 noteligible.