This is a Phase II open-label study to investigate the safety and efficacy of ACT001 in patients with DIPG and H3K27-altered HGG.

Patients will be enrolled on either Cohort A for newly diagnosed DIPG or on Cohort B for those with progressive / refractory DIPG or progressive / recurrent / refractory H3K27-altered HGG. Each cohort will receive ACT001 at 875 mg/m2 orally BID for 28 days (1 cycle of treatment), up to a maximum dose of 1700 mg BID. If patients are experiencing clinical benefit from study therapy, they will continue to receive ACT001 in repeat 28-day cycles for up to 26 cycles (approximately 2 years) or until disease progression, whichever occurs first. Continuation of treatment beyond 26 cycles may be considered if patients are receiving clinical benefit from the study, at the discretion of the sponsor and treating physician.

Inclusion Criteria:

1. Patients must be ≥ 12 months and ≤ 39 years of age at the time of study enrollment.

2. Diagnosis:

   • Cohort A: Newly Diagnosed DIPG

     • Patients with newly-diagnosed DIPG with typical MRI findings (tumors with a pontine epicenter and diffuse involvement of at least 2/3 of the pons) with or without biopsy and have completed radiation therapy (RT) within 28 to 35 calendar day prior to start of therapy.

     • Patients must have started RT <42 calendar days from radiographic diagnosis (for non-biopsied DIPG patients only) or definitive surgery, whichever is later.

       • If a biopsy was performed, the date of surgical biopsy will be considered the date of definitive diagnostic surgery; if a patient underwent two upfront surgeries [e.g., biopsy then debulking], this is the date of the second surgery)

   • Cohort B: progressive/recurrent DIPG or H3K27-altered HGG OR refractory disease

     • Patients with DIPG (no biopsy required), pathologically-confirmed (at diagnosis or recurrence) H3K27-altered DIPG, or extra-pontine H3K27-alteredHGG who have progressive/recurrent or refractory disease
     • Progressive/recurrent: patients who have progressive or recurrent disease following frontline treatment must have included at least focal RT. New lesions since completion of frontline RT qualify as progressive disease.
     • Refractory disease is defined as: Presence of persistent, measurable, abnormality on conventional MRI that is further distinguished by histology or advanced imaging, OR as determined by the treating physician and discussed with the Study Chair(s) prior to enrollment.
     • Patients with H3K27-altered spinal HGG are eligible.
     • Patients with metastatic disease are eligible.

3. Disease Status

   • Cohort A: patients may have any disease status but must have completed initial radiation therapy (RT) before enrollment.
   • Cohort B: Patients must have measurable disease assessable by MRI. Patients may have extra neuronal disease.

4. Performance Level: Karnofsky Performance Scale score ≥ 50% for patients > 16 years of age and Lansky Performance Scale score > 50% for patients ≤ 16 years of age (applies to all patients) Note: Patients who are unable to walk because of paralysis, but who are capable of using a wheelchair, will be considered ambulatory for the purpose of assessing the performance score.

5. Prior anti-cancer therapy:

   • For Cohort A ONLY:
   • Surgery, radiation (focal to disease) and/or steroids (dexamethasone with goal to wean dexamethasone throughout protocol therapy) are permissible. Temozolomide administered concurrently with RT is permissible. Bevacizumab use is permitted given the last dose was administered >/= 21 days prior to enrollment. No other prior anticancer therapy for DIPG will be allowed.
   • Patients must enroll and start treatment on study between 28 and 35 calendar days post-completion of RT.
   • Patients must have started RT <42 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).
   • Radiotherapy must have been administered at standard dose of 54 Gy for DIPG patients. 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.
   • For Cohort B ONLY: Patients must have fully recovered from the acute treatment related toxicities (defined as </= Grade 1 if not defined in eligibility criteria) of all prior chemotherapy, immunotherapy, radiotherapy, or any other treatment modality prior to entering on this study, with the exception of alopecia.

   Notes to the above for Cohort B: Patients with chronic Grade 2 toxicities may be eligible per discretion of the Investigator and Sponsor (e.g., Grade 2 chemotherapy-induced neuropathy). Grade 2 or 3 toxicities from prior anti-tumor therapy that are considered irreversible - defined as having been present and stable for > 6 months (such as ifosfamide-related proteinuria) may be allowed if they are not otherwise described in the exclusion criteria AND there is agreement to allow by both the Investigator and Sponsor.)

   The wash out period between the prior anti-cancer chemotherapy, and enrollment must be:

   1. Myelosuppressive chemotherapy: At least 21 days after the last dose of myelosuppressive chemotherapy (42 days if prior nitrosourea).

   2. Hematopoietic growth factors: At least 14 days after the last dose of a long-acting growth factor (e.g. Neulasta) or 7 days for short-acting growth factor.

   3. Biologic (anti-neoplastic agent): At least 7 days after the last dose of a biologic agent. For agents that have known adverse events occurring beyond 7 days after administration, this period must be extended beyond the time during which adverse events are known to occur. The duration of this interval must be discussed with the study chair.

   4. Immunotherapy: At least 42 days after the completion of any type of immunotherapy, e.g. tumor vaccines.

   5. Monoclonal antibodies: > 21 days must have elapsed from the infusion of last dose of antibody

   6. Radiation therapy:

      • All Cohort B patients: Patients must have received their last fraction of focal irradiation to new sites of progressive disease > 14 days prior to enrollment.

        • Patients who received CSI must have received their last fraction > 3 months prior to enrollment.

      • Progressive/recurrent disease: Patients who received re-irradiation to primary disease must have received their last fraction > 3 months prior to study enrollment.

      • Refractory Disease:

        • Patients must have completed frontline RT > 6 months prior to enrollment.
        • Patients who received re-irradiation to primary disease must have received their last fraction > 3 months prior to study enrollment.

   7. Stem Cell Transplant: Patients must be ≥ 3 months since autologous stem cell transplant. Patients who received allogenic stem cell transplant or solid organ transplant are not eligible for study

6. Organ Function Requirements (applies to all patients)

   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)

   2. Adequate renal function defined as:

      • Creatinine clearance or radioisotope GFR ≥ 70 mL/min/1.73 m² or
      • A serum creatinine based on age/gender as follows (Schwartz et al. J. Peds, 106:522, 1985): Age Maximum Serum Creatinine (mg/dL) Male Female 1 to < 2 years 0.6 0.6 2 to < 6 years 0.8 0.8 6 to < 10 years 1.0 1.0 10 to < 13 years 1.2 1.2 13 to < 16 years 1.5 1.4 ≥ 16 years 1.7 1.4

   3. Adequate liver function defined as:

      • total bilirubin must be \