Beurteilung der Sicherheit und Wirksamkeit von ONC206 bei Kindern mit bösartigen Hirntumoren

Drug: ONC206;Radiation: Standard of Care Radiation Therapy

Gender: All
Maximum age: 21 Years
Minimum age: 2 Years

Inclusion Criteria:

- ARM A: Children and young adults with DMG, H3K27 altered (Dose escalation: 2-21 years
of age; Dose expansion: 2 years of age and above) who completed at least one line of
prior therapy. Prior treatment must have included focal radiation therapy and patients
must be within 4-14 weeks from completion of radiation therapy to registration
(patients must start treatment within 1 week from registration), have not started any
other therapies post-radiation, and have no evidence of disease progression.

- ARM A: Tumor tissue confirmation of DMG, H3K27 altered is mandatory and pathology must
be consistent with a DMG, H3K27 altered.

- ARM A: Participants must have recovered from all acute side effects of prior therapy.

- ARM A: From the projected start of scheduled study treatment, the following time
periods must have elapsed: 5 half-lives from any investigational agent, 4 weeks from
cytotoxic therapy (except 23 days for temozolomide and 6 weeks from nitrosoureas), 4
weeks from antibodies and must be at least 7 days since the completion of therapy with
a biologic or small molecule agent. For any biologic or small molecule agent with
known adverse events that can occur beyond 7 days after administration, the period
prior to enrollment must be beyond the time during which adverse events are known to
occur (these should be discussed with the study team)

- ARM B: Newly diagnosed children and young adults (Dose escalation: 2-21 years of age;
Dose expansion: 2 years of age and above) with a diagnosis of DMG, H3K27 altered are
eligible, including spinal cord DMGs.

- ARM B: Tumor tissue confirmation of DMG is mandatory and pathology must be consistent
with a DMG, H3K27 altered.

- ARM C: Children and young adults with DMGs (Dose escalation: 2-21 years of age; Dose
expansion: 2 years of age and above) who have evidence of progression but have not
been treated for this progression and are recommended to get re-irradiation.

- ARM C: Patients must have undergone prior focal radiation therapy as part of their
initial therapy and should be at least 6 months from prior radiation therapy. If
timing is less than 6 months from prior focal radiation, these patients need to be
discussed with the study chair(s).

- ARM C: Tumor tissue confirmation is mandatory and pathology must be consistent with a
DMG, H3K27 altered.

- ARM C: Participants must have recovered from all acute side effects of prior therapy

- ARM C: From the projected start of scheduled study treatment, the following time
periods must have elapsed: 5 half-lives from any investigational agent, 4 weeks from
cytotoxic therapy (except 23 days for temozolomide and 6 weeks from nitrosoureas), 4
weeks from antibodies and must be at least 7 days since the completion of therapy with
a biologic or small molecule agent. For any biologic or small molecule agent with
known adverse events that can occur beyond 7 days after administration, the period
prior to enrollment must be beyond the time during which adverse events are known to
occur (these should be discussed with the study team)

- ARM D: Children and young adults with recurrent primary malignant CNS tumors (Dose
escalation: 2-21 years of age; Dose expansion: 2 years of age and above ) who have
evidence of progression but have not been treated for this progression . Participants
who received a surgical resection for that progression are eligible if surgery has no
curative intent. These patients need to be discussed with the study team.

- ARM D: Prior tumor tissue confirmation is mandatory and pathology from the primary
tumor must be consistent with malignant CNS tumor (diagnosis of ependymoma is
allowed).Tissue at the time of progression is not required.

- ARM D: Participants must have recovered from all acute side effects of prior therapy

- ARM D: From the projected start of scheduled study treatment, the following time
periods must have elapsed: 5 half-lives from any investigational agent, 4 weeks from
cytotoxic therapy (except 23 days for temozolomide and 6 weeks from nitrosoureas), 4
weeks from antibodies and must be at least 7 days since the completion of therapy with
a biologic or small molecule agent. For any biologic or small molecule agent with
known adverse events that can occur beyond 7 days after administration, the period
prior to enrollment must be beyond the time during which adverse events are known to
occur (these should be discussed with the study team). Bevacizumab used for
pseudoprogression does not require a wash out period.

- TARGET VALIDATION: Newly diagnosed children and adults (2 years of age and above) with
imaging consistent with a DMG, H3K27 altered are eligible.

- TARGET VALIDATION: Children and young adults with recurrent primary malignant CNS
tumors, including recurrent DMG, (2 years of age and above) who have evidence of
progression but have not been treated for this progression.

- TARGET VALIDATION: Participants must undergo tumor tissue collection as part of their
standard of care

- Participants who are receiving steroids must be on a stable or decreasing dose for at
least 3 days prior to baseline MRI scan.

- Peripheral absolute neutrophil count (ANC) >= neutrophil 1.0 g/l.

- Platelet count >= 100 x 10^9/L (transfusion independent, defined as not receiving
platelet transfusions for at least 7 days prior to enrollment).

- Serum creatinine < 1.5 Upper Limit normal (ULN) based on age and gender.

- Total bilirubin <= 1.5 x upper limit of normal (ULN) for age; in presence of Gilbert's
syndrome, total bilirubin < 3 x ULN or direct bilirubin < 1.5 x ULN.

- Alanine aminotransferase (ALT) <= 3 x ULN.

- Aspartate aminotransferase (AST) <= 3 x ULN.

- Patients with seizure disorder may be enrolled if seizure disorder is well controlled

- The effects of ONC206 on the developing human fetus is unknown. For this reason,
females of child-bearing potential and males must agree to use adequate contraception.
Adequate methods include: hormonal or barrier method of birth control; or abstinence
prior to study entry and for the duration of study participation. Should a woman
become pregnant or suspect she is pregnant while she or her partner is participating
in this study, she should inform her treating physician immediately. Males treated or
enrolled on this protocol must also agree to use adequate contraception prior to the
study and for the duration of study participation

- Karnofsky >= 50 for participants > 16 years of age and