A Study Comparing Abemaciclib Plus Temozolomide to Temozolomide Monotherapy in Children and Young Adults With High-grade Glioma Following Radiotherapy

Inclusion Criteria:

• Biopsy proven high-grade glioma (HGG) as defined by 2016 World Health Organization (WHO) Classification Criteria, Grade 3-4 including:

• Anaplastic astrocytoma

• Anaplastic ganglioglioma

• Anaplastic oligodendroglioma.

• Anaplastic pleomorphic xanthoastrocytoma,

• Glioblastoma

OR as defined by the 2021 WHO Classification Criteria as molecularly characterized:

• Non-pontine diffuse midline glioma, H3 K27-altered,

• Diffuse hemispheric glioma, H3 G34-mutant

• Diffuse pediatric HGG, H3/IDH-wildtype

• Infant-type hemispheric glioma

• High-grade astrocytoma with piloid features

• High-grade pleomorphic xanthoastrocytoma

• IDH-mutant diffuse glioma with homozygous cyclin- dependent kinase inhibitor 2A/B (CDKN2A/B) deletion,

• IDH-mutant and 1p/19q co-deleted oligodendroglioma

• IDH-mutant astrocytoma with homozygous CDKN2A/B deletion

• Contraceptive use should be consistent with local regulations for participants inclinical studies.

• Radiotherapy initiated within 6 weeks (+1 week) of diagnosis and administered over 6weeks (±1 week). Participants <3 years of age, considered not suitable forradiotherapy may be eligible.

• Minimum of 4 weeks between completion of radiation and Cycle 1 Day 1 (C1D1).

• Maximum of 8 weeks between completion of radiation and C1D1. Exceptionalcircumstances can be discussed with the medical monitor.

• Acute effects of prior therapies must be Grade ≤1 unless deemed clinicallyinsignificant by the investigator.

• Adequate hematologic and organ function ≤7 days prior to C1D1

• Life expectancy of ≥8 weeks and deemed likely to complete at least 1 cycle oftreatment.

• A performance score of ≥60 using:

1. Lansky scale for participants <16 years

2. Karnofsky scale for participants ≥16 years

• Able to swallow and/or have a gastric/nasogastric tube.

• Any current systemic steroid use dose must be stable or decreasing at least 7 daysprior to C1D1.

• Able and willing to adhere to study procedures, including frequent blood draws andMRI.

• At least 28 days since any major surgery, laparoscopic procedure, or a significanttraumatic injury.

• Has a body surface area (BSA) of ≥0.2 m2.

Exclusion Criteria:

Participants are excluded if any of the following apply:

• Diffuse Intrinsic Pontine Glioma (DIPG) or diffuse midline glioma located in thepons.

• Recurrent or refractory HGG including any recurrence/progression during/afterradiotherapy.

• Secondary HGG, defined as a previously treated low-grade glioma that now meets high-grade criteria, or that resulted from a previously treated malignancy.

• Have known pathogenic somatic mutations appropriate for an anaplastic lymphomakinase (ALK), B-rapidly accelerated fibrosarcoma (BRAF), or neurotrophic tyrosinereceptor kinase (NTRK ) inhibitor, in regions where these therapies are availableand deemed appropriate by the investigator.

• Prior HGG treatment (including bevacizumab), except for surgery and radiotherapy (with or without concomitant temozolomide).

• Current enrollment in another trial deemed incompatible with this study.

• Treatment with an investigational product within the last 30 days or 5 half-lives (whichever is longer).

• Prior malignancy within the previous 3 years that, per the investigator and themedical monitor, may affect interpretation of study results.

• A preexisting medical condition(s) that, per the investigator, would preclude studyparticipation.

• Any serious, active, systemic infection requiring IV antibiotic, antifungal, orantiviral therapy, including acute hepatitis B or C, or Human Immunodeficiency Virusat C1D1.

• Intolerability or hypersensitivity such as urticaria, anaphylaxis, toxic necrolysis,and/or Stevens-Johnson syndrome to temozolomide, and/or abemaciclib, theirexcipients, or dacarbazine.

• Received a live virus vaccine within 28 days of C1D1.

• Pregnant, breastfeeding, or intend to become pregnant during the study.