PRIMARY OBJECTIVES:
I. To determine the safety and tolerability of DRD2 antagonist/ClpP agonist ONC206 (ONC206).
II. To determine the maximum tolerated dose (MTD) of ONC206 as single agent in children and
young adults with diffuse midline glioma (DMG) who completed at least one line of prior
therapy that included focal radiation therapy. (Arm A).
III. To determine the MTD of ONC206 in combination with focal radiation therapy in newly
diagnosed children and young adults with DMG. (Arm B).
IV. To determine the MTD of ONC206 in combination with re-irradiation in children and young
adults with first progression of DMG. (Arm C).
V. To determine the MTD of ONC206 in children and young adults with recurrent primary
malignant brain tumors including participants with recurrent DMGs if they are not eligible
for the other arms. (Arm D).
VI. To assess the concentration of ONC206 in tumor tissue from children and young adults with
DMG and compare to plasma drug levels pre-surgery. (Target validation).
VII. To assess the concentration of ONC206 in tumor tissue in children and young adults with
recurrent primary malignant brain tumors and compare to plasma drug levels pre-surgery.
(Target validation).
SECONDARY OBJECTIVE:
I. To describe the pharmacokinetics associated with ONC206 without radiation therapy. (Arms A
and D).
EXPLORATORY OBJECTIVES:
I. Determine changes in cranial nerve scoring.
II. Determine clinical responses within the confines of a phase 1/expansion study.
III. Evaluate correlation of amount of serum and cerebrospinal fluid (CSF) circulating tumor
DNA (ctDNA) with clinical outcome.
IV. Evaluate association of clinical outcomes with anatomic location of tumor, H3K27 mutation
status and other partner mutations.
V. Pharmacodynamic (PD) effects in tumor tissue.
VI. Assess the overall response rate to ONC206 in patients with prior ONC201 exposure.
VII. Assess pharmacodynamics (PD) of ONC206 and perform exploratory pharmacokinetic (PK)-PD
analyses to investigate and identify the relationship between drug exposure and clinical
endpoints for both safety and efficacy.
VIII. To assess Health Related Quality of Life (HRQOL) outcomes.
VIIII. To assess patient and/or proxy satisfaction with study participation via
patient-reported outcome (PRO) measures
OUTLINE: This is a dose-escalation study of ONC206. Patients are assigned to 1 of 4 arms.
ARMS A and D: Patients receive ONC206 orally (PO) once daily (QD) on days 1, 8, 15, 22.
Cycles repeat every 28 days for up to 12 months in the absence of disease progression or
unacceptable toxicity.
ARMS B and C: Patients undergo standard of care radiation therapy daily 5 days a week and
receive ONC206 as in Arm A.
After completion of study treatment, patients are followed up at 30 days and then every 3
months for up to 5 years.
Inclusion Criteria:
- ARM A: Children and young adults with DMG (2-21 years of age) 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 and have
no evidence of disease progression
- ARM A: Tumor tissue confirmation of DMG is mandatory and pathology must be consistent
with a DMG including DMG H3K27M mutant and World Health Organization (WHO) grade III
and IV H3 wildtype gliomas. WHO grade II diffuse astrocytomas or other low grade
gliomas without H3K27M mutation are not eligible
- ARM A: Participants must have recovered from all acute side effects of prior therapy.
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 (2-21 years of age) with a diagnosis
of DMG are eligible, including spinal cord DMGs
- ARM B: Tumor tissue confirmation of DMG is mandatory and pathology must be consistent
with a DMG including DMG H3K27M mutant and WHO grade III and IV H3 wildtype gliomas.
WHO grade II diffuse astrocytomas or other low grade gliomas without H3K27M mutation
are not eligible
- ARM C: Children and young adults with DMGs (2-21 years of age) who have evidence of
first progression but have not been treated for this progression and are recommended
to get reirradiation
- 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 of DMG is mandatory and pathology must be consistent
with a DMG including DMG H3K27M mutant and WHO grade III and IV H3 wildtype gliomas.
WHO grade II diffuse astrocytomas or other low grade gliomas without H3K27M mutation
are not eligible
- 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 brain tumors (2 - 21
years of age) who have evidence of progression but have not been treated for this
progression
- ARM D: Tumor tissue confirmation is mandatory and pathology must be consistent with
recurrent primary malignant brain tumor (diagnosis of recurrent ependymoma is allowed)
- 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)
- ARM D: Participants who are receiving dexamethasone must be on a stable or decreasing
dose for at least 3 days prior to baseline magnetic resonance imaging (MRI) scan
- TARGET VALIDATION: Newly diagnosed children and adults (2 years of age and above) with
imaging consistent with a DMG are eligible
- TARGET VALIDATION: Children and young adults with recurrent primary malignant brain
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)
- Creatinine clearance or radioisotope glomerular filtration rate (GFR) >= 90
mL/min/1.73 m^2 or a serum creatinine based on age/gender equal upper limit of normal
- Bilirubin (sum of conjugated + unconjugated) =< 1.5 x upper limit of normal (ULN) for
age
- Serum glutamic pyruvic transaminase (SGPT) (alanine aminotransferase (ALT)) =< 2 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 Lansky >= 50 for participants
=< 16 years of age. Participants 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
- Subjects must be willing to provide archival formalin-fixed embedded (FFPE) and frozen
tissue specimens for biomarker studies, if available
- A legal parent/guardian or participant must be able to understand, and willing to
sign, a written informed consent and assent document, as appropriate
Exclusion Criteria:
- Participants who are currently receiving another investigational drug are not eligible
- Participants who are currently receiving other anti-cancer agents are not eligible
- Participants with a known disorder that affects their immune system, such as human
immunodeficiency virus (HIV) or hepatitis B or C, or an auto-immune disorder requiring
systemic cytotoxic or immunosuppressive therapy are not eligible. Note: Participants
that are currently using inhaled, intranasal, ocular, topical or other non-oral or
non-intravenous (IV) steroids are not necessarily excluded from the study but need to
be discussed with the study chair
- Participants with uncontrolled infection
- Female participants of childbearing potential must not be pregnant or breast-feeding.
Female participants of childbearing potential must have a negative serum or urine
pregnancy test prior to the start of therapy
- Active illicit drug use or diagnosis of alcoholism
- History of allergic reactions attributed to compounds of similar chemical or biologic
composition to ONC206
- Inability to follow the procedures of the study, e.g. due to language problems,
psychological disorders, dementia, etc. of the participant or family
- Any participants with illnesses that may affect absorption of ONC206
- Any participants on strong inhibitors or inducers of CYP3A4, 2D6, 1A2, 2C9 and 2C19 at
least 14 days prior and throughout the study
