Vorasidenib in Combination With Temozolomide (TMZ) in IDH-mutant Glioma

Inclusion Criteria:

• Be ≥12 years of age with a weight at screening ≥40 kg.

• Have documented IDH1 or IDH2 mutation based on local testing of tumor tissue by anaccredited laboratory

• Have adequate renal function, defined as a creatinine clearance ≥40 mL/min based onthe Cockcroft-Gault glomerular filtration rate estimation: (140 - Age) × (Weight inkg) × (0.85 if female) / 72 × serum creatinine (mg/dL).

• Have adequate bone marrow function as evidenced by:

1. Absolute neutrophil count ≥1,500/mm3 or 1.5×109/L

2. Hemoglobin ≥9 g/dL or 90 g/L

3. Platelets ≥100,000/mm3 or 100×109/L

• Have expected survival of ≥3 months.

• KPS or LPPS ≥70 at the start of study treatment.

• Participants on corticosteroids for reasons related to glioma must be on a stable ordecreasing dose (≤4mg/day dexamethasone or equivalent) for ≥5 days before the startof study treatment.

• Female participants of reproductive potential must have a negative serum pregnancytest before starting study treatment.

Phase 1b ONLY:

• Have histologically confirmed Grade 2, 3 or 4 IDHm (as per WHO 2021) glioma (astrocytoma or oligodendroglioma).

1. For oligodendroglioma: Have local testing at an accredited laboratorydemonstrating presence of 1p19q co deletion

2. For astrocytoma: Have local testing by an accredited laboratory demonstratinglack of 1p19q co-deletion and/or documented loss of nuclear ATRX expression orATRX mutation

• Are appropriate to receive TMZ as post-radiotherapy (RT) adjuvant therapy or astreatment for first disease recurrence after prior RT and/or chemotherapy, perInvestigator judgement. For those receiving TMZ in the post-RT adjuvant setting,study treatment must begin no more than 6 weeks after completion of RT.

• Have adequate hepatic function as evidenced by:

1. Serum total bilirubin ≤1.5×upper limit of normal (ULN); if ≥1.5×ULN and due toGilbert syndrome, total bilirubin ≤3×ULN with direct bilirubin ≤ULN,

2. AST and ALT ≤ULN, and

3. Alkaline phosphatase ≤2.5×ULN.

Phase 2 ONLY:

• Have histologically confirmed Grade 4 astrocytoma, IDHm (per 2021 WHO criteria).Those who meet the Grade 4 designation via homozygous deletion of CDKN2A/B areeligible.

• Have absence of 1p19q co-deletion (i.e., non-co-deleted, or intact) and/ordocumented loss of nuclear ATRX expression or ATRX mutation by local testing.

• Have received SOC RT with concurrent TMZ (RT-TMZ) before enrollment. Study treatmentmust begin no more than 6 weeks after completion of RT-TMZ.

• Have adequate hepatic function as evidenced by:

1. Serum total bilirubin ≤1.5×ULN; if ≥1.5×ULN and due to Gilbert syndrome, totalbilirubin ≤3×ULN with direct bilirubin ≤ULN,

2. AST and ALT at or below the upper limit of normal. An elevation ≤1.5×ULN andconsidered not clinically significant by the Investigator may be allowed afterMedical Monitor (Sponsor) approval, and

3. Alkaline phosphatase ≤2.5×ULN.

Exclusion Criteria:

• Unable to swallow oral medication.

• Are pregnant or breastfeeding.

• Are participating in another interventional study at the same time; participation innon-interventional registries or epidemiological studies is allowed.

• Have leptomeningeal disease.

• Have a known coagulopathy.

• Received prior therapy with an IDH inhibitor, IDH-directed vaccine, or bevacizumab.

• Have a history of another concurrent primary cancer, with the exception of:

1. curatively resected non-melanoma skin cancer, or

2. curatively treated carcinoma in situ. Participants with other previouslytreated malignancies are eligible provided they have been disease-free for 3years at Screening.

• Have adequate bone marrow function as evidenced by:
 

1. Absolute neutrophil count ≥1,500/mm3 or 1.5×109/L
 
2. Hemoglobin ≥9 g/dL or 90 g/L
 
3. Platelets ≥100,000/mm3 or 100×109/L
 

• Have expected survival of ≥3 months.
 
• KPS or LPPS ≥70 at the start of study treatment.
 
• Participants on corticosteroids for reasons related to glioma must be on a stable or
decreasing dose (≤4mg/day dexamethasone or equivalent) for ≥5 days before the start
of study treatment.
 
• Female participants of reproductive potential must have a negative serum pregnancy
test before starting study treatment.
 
 Phase 1b ONLY:
 
• Have histologically confirmed Grade 2, 3 or 4 IDHm (as per WHO 2021) glioma
 (astrocytoma or oligodendroglioma).
 

1. For oligodendroglioma: Have local testing at an accredited laboratory
demonstrating presence of 1p19q co deletion
 
2. For astrocytoma: Have local testing by an accredited laboratory demonstrating
lack of 1p19q co-deletion and/or documented loss of nuclear ATRX expression or
ATRX mutation
 

• Are appropriate to receive TMZ as post-radiotherapy (RT) adjuvant therapy or as
treatment for first disease recurrence after prior RT and/or chemotherapy, per
Investigator judgement. For those receiving TMZ in the post-RT adjuvant setting,
study treatment must begin no more than 6 weeks after completion of RT.
 
• Have adequate hepatic function as evidenced by:
 

1. Serum total bilirubin ≤1.5×upper limit of normal (ULN); if ≥1.5×ULN and due to
Gilbert syndrome, total bilirubin ≤3×ULN with direct bilirubin ≤ULN,
 
2. AST and ALT ≤ULN, and
 
3. Alkaline phosphatase ≤2.5×ULN.
 
 Phase 2 ONLY:
 

• Have histologically confirmed Grade 4 astrocytoma, IDHm (per 2021 WHO criteria).
Those who meet the Grade 4 designation via homozygous deletion of CDKN2A/B are
eligible.
 
• Have absence of 1p19q co-deletion (i.e., non-co-deleted, or intact) and/or
documented loss of nuclear ATRX expression or ATRX mutation by local testing.
 
• Have received SOC RT with concurrent TMZ (RT-TMZ) before enrollment. Study treatment
must begin no more than 6 weeks after completion of RT-TMZ.
 
• Have adequate hepatic function as evidenced by:
 

1. Serum total bilirubin ≤1.5×ULN; if ≥1.5×ULN and due to Gilbert syndrome, total
bilirubin ≤3×ULN with direct bilirubin ≤ULN,
 
2. AST and ALT at or below the upper limit of normal. An elevation ≤1.5×ULN and
considered not clinically significant by the Investigator may be allowed after
Medical Monitor (Sponsor) approval, and
 
3. Alkaline phosphatase ≤2.5×ULN.
 
 Exclusion Criteria:
 

• Unable to swallow oral medication.
 
• Are pregnant or breastfeeding.
 
• Are participating in another interventional study at the same time; participation in
non-interventional registries or epidemiological studies is allowed.
 
• Have leptomeningeal disease.
 
• Have a known coagulopathy.
 
• Received prior therapy with an IDH inhibitor, IDH-directed vaccine, or bevacizumab.
 
• Have a history of another concurrent primary cancer, with the exception of:
 

1. curatively resected non-melanoma skin cancer, or
 
2. curatively treated carcinoma in situ. Participants with other previously
treated malignancies are eligible provided they have been disease-free for 3
years at Screening.
 

• Have a known diagnosis of replication repair-deficient glioma (e.g., a knowndiagnosis of constitutional mismatch repair deficiency or Lynch syndrome).

• Have a known hypersensitivity to any of the components or metabolites of vorasidenibor TMZ.

• Have significant active cardiac disease within 6 months before Screening, includingNew York Heart Association (NYHA) Class III or IV congestive heart failure,myocardial infarction, unstable angina, and/or stroke.

• Have heart rate corrected QT interval (using Fridericia's formula) (QTcF) ≥450 msecor have other factors that increase risk of QT prolongation or arrhythmic events (e.g., heart failure, hypokalemia, family history of long QT interval syndrome).Right bundle branch block and prolonged QTcF interval may be permitted based onlocal cardiology assessment.

• Have known active hepatitis B (HBV) or hepatitis C (HCV) infections, known positivehuman immunodeficiency virus (HIV) antibody results, or acquired immunodeficiencysyndrome (AIDS) related illness. Participants with a sustained viral response to HCVtreatment or immunity to prior HBV infection will be permitted. Participants withchronic HBV or HIV that is adequately suppressed per institutional practice will bepermitted.

Phase 1b ONLY:

• For those receiving TMZ in the frontline post-RT adjuvant setting: Have progressivedisease during RT or after completion of SOC RT and before the start of studytreatment.

• For those receiving TMZ in the recurrent disease setting:

1. Have received prior systemic anti-cancer therapy (other than surgery) within 1month (or 6 weeks for nitrosoureas and 6 months for TMZ) of the start of studytreatment. In addition, the first dose of study treatment should not occurbefore a period of 28 days or ≥5 half-lives of any prior investigational agenthave elapsed, whichever is longer.

2. Have received more than one prior line of therapy for glioma (Note: prior RT +chemotherapy is considered one line of therapy).

• Had Grade ≥2 hepatic-related toxicity (AST, ALT, and/or bilirubin elevations) duringprior systemic chemotherapy

• Had Grade 4 hematologic toxicity (excluding lymphopenia) that did not recover within 7 days during a prior course of TMZ

Phase 2 ONLY:

• Have received any other glioma-directed therapy other than surgery and SOC RT-TMZ

• Have progressive disease during RT-TMZ or after completion of SOC RT-TMZ and beforethe start of study treatment.

• Had Grade 4 hematologic toxicity (excluding lymphopenia) that did not recover within 7 days during concurrent RT-TMZ

• Had Grade ≥2 hepatic-related toxicity (AST, ALT, and/or bilirubin elevations) duringconcurrent RT-TMZ