PNOC023: Open Label Phase 1 and Target Validation Study of ONC206 in Children and Young Adults with Newly Diagnosed or Recurrent Diffuse Midline Glioma (DMG), and Other Recurrent Primary Malignant Central Nervous System (CNS) Tumors.

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Prinses Maxima Centrum voor Kinderoncologie B.V.

Participant type

Pediatric, Patients

Age range

0-17 years, 18-64 years

Gender

Male and Female

Therapeutic area

Diseases [C] - Neoplasms [C04]

Trial duration

4 Mar 2026 → ongoing

Decision date (initial)

2025-12-08

Transition trial

No

Low-intervention

No

Rare-disease indication

Yes

Vulnerable population

Yes

External identifiers

EU CT number

2025-521180-13-00

ClinicalTrials.gov

NCT04732065

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Efficacy, Therapy, Pharmacokinetic, Safety, Pharmacodynamic

Dose escalation and dose expansion:
-Arm A: To determine the maximum tolerated dose (MTD) of ONC206 as single agent in children and young adults with DMG, H3K27 altered, who completed at least one line of prior therapy that included focal radiation therapy.
-Arm B: To determine the MTD of ONC206 in combination with focal radiation therapy in newly diagnosed children and young adults with DMG, H3K27 altered.
-Arm C: To determine the MTD of ONC206 in combination with re-irradiation in children and young adults with progression of DMG, H3K27 altered.
-Arm D: To determine the MTD of ONC206 in children and young adults with recurrent primary malignant CNS tumors.

Target Validation:
-Arm A-C: To assess the concentration of ONC206 in tumor tissue from children and young adults with DMG, H3K27 altered predominantly localized to the thalamus, to the pons, and in non-thalamic and non-pontine locations, and compare to plasma drug levels pre-surgery.
-Arm D: To assess the concentration of ONC206 in tumor tissue in children and young adults with recurrent primary malignant CNS tumors and compare to plasma drug levels pre-surgery.

Secondary objectives 1

1. To characterize the PK of ONC206 in plasma in patients with DMG, H3K27 altered and recurrent primary malignant CNS tumors.

Conditions and MedDRA coding

Diffuse Midline Glioma (DMG), and Other Recurrent Primary Malignant Central Nervous System (CNS) Tumors

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 25

1. 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).
2. Arm A: Tumor tissue confirmation of DMG, H3K27 altered is mandatory and pathology must be consistent with a DMG, H3K27 altered.
3. Arm A: Participants must have recovered from all acute side effects of prior therapy.
4. 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 enrolment must be beyond the time during which adverse events are known to occur (these should be discussed with the study team).
5. 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.
6. Arm B: Tumor tissue confirmation of DMG is mandatory and pathology must be consistent with a DMG, H3K27 altered.
7. 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.
8. 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).
9. Arm C: Tumor tissue confirmation is mandatory and pathology must be consistent with a DMG, H3K27 altered
10. Arm C: Participants must have recovered from all acute side effects of prior therapy.
11. 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).
12. Arm D: Children and young adults with recurrent primary malignant CNS tumors, excluding 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 . 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.
13. 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.
14. Arm D: Participants must have recovered from all acute side effects of prior therapy.
15. 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.
16. Target validation, arm A-B: Newly diagnosed children and adults (2 years of age and above) with imaging consistent with a DMG, H3K27 altered are eligible.
17. Target validation, arm C-D: 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.
18. Target validation, all participants: Participants must undergo tumor tissue collection as part of their standard of care.
19. All participants: Corticosteroids: Participants who are receiving steroids must be on a stable or decreasing dose for at least 3 days prior to registration.
20. All participants: The patient must have adequate organ function defined as: • Adequate Bone Marrow Function Defined as: - Peripheral absolute neutrophil count (ANC) ≥ Neutrophil 1.0 g/l and - Platelet count ≥ 100 109/l (transfusion independent, defined as not receiving platelet transfusions for at least 7 days prior to enrollment). • Adequate Renal Function Defined as: - A serum creatinine < 1.5 Upper Limit normal (ULN) based on age and gender. • Adequate Liver Function Defined as: - 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 - ALT ≤ 3 x ULN - AST ≤ 3 x ULN • Adequate Neurologic Function Defined as: - Patients with seizure disorder may be enrolled if seizure disorder is well controlled.
21. All participants: The effects of ONC206 on the developing human fetus are 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.
22. All participants: 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.
23. All participants: Participants must be willing to provide adequate tissue. A minimum of 10-20 paraffin embedded unstained slides OR 1 block with tumor content of 40% or greater is required. Frozen tissue is also acceptable. Participants who previously enrolled on PNOC022 and provided adequate tissue, may not need to submit additional tissue – confirm with Study Chairs. Participants who do not meet this criteria may be discussed on a case-by-case basis with the Study Chairs.
24. All participants: A legal parent/guardian or participant must be able to understand, and willing to sign, a written informed consent and assent document, as appropriate.
25. All participants dose: Patients must enroll on PNOC COMP if PNOC COMP is open to accrual at the enrolling institution.

Exclusion criteria 12

1. Arm A-B: For tumors that do not have a pontine or spinal cord epicenter the following specific exclusion criteria apply: • Thalamic DMG and cerebellar, H3K27 altered that has undergone standard radiation without concurrent therapy (other than temozolomide)
2. Arm C-D: Patients who participated in trials investigating ONC201 in the upfront setting will not be eligible. Prior ONC201 exposure as part of PNOC022 or expanded access programs will be allowed.
3. All Participants: Investigational Drugs: Participants who are currently receiving another investigational drug are not eligible.
4. All Participants: Anti-cancer Agents: Participants who are currently receiving other anti-cancer agents are not eligible.
5. All Participants: Participants with a known disorder that affects their immune system, such as 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-IV steroids are not necessarily excluded from the study but need to be discussed with the study chair.
6. All Participants: Participants with uncontrolled infection or other uncontrolled systemic illness.
7. All Participants: 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.
8. All Participants: Active illicit drug use or diagnosis of alcoholism.
9. All Participants: History of allergic reactions attributed to compounds of similar chemical or biologic composition to ONC206
10. All Participants: Inability to follow the procedures of the study, e.g. due to language problems, psychological disorders, dementia, etc. of the participant or family.
11. All Participants: Any Participants with illnesses that may affect absorption of ONC206.
12. All Participants: Any participants on strong inhibitors or inducers of CYP3A4, 2D6, 2C8, 2C9, and 2B6 at least 14 days prior and throughout the study.

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 2

1. Dose escalation and expansion phase: MTD (Maximum tolerated dose); within the first 4 weeks of treatment for Arms A and D (without radiation) and the duration of radiation for Arms B and C (in combination with radiation)
2. Target validation arms: Measurement for determining if the study drug passes the blood brain barrier and enters the tumor

Secondary endpoints 1

1. Pharmacokinetic (PK) assessments for ONC206

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 1

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Prinses Maxima Centrum voor Kinderoncologie B.V.

Sponsor organisation

Prinses Maxima Centrum voor Kinderoncologie B.V.

Address

Heidelberglaan 25

City

Utrecht

Postcode

3584 CS

Country

Netherlands

Scientific contact point

Organisation

Prinses Maxima Centrum voor Kinderoncologie B.V.

Contact name

Jasper van der Lugt

Public contact point

Organisation

Prinses Maxima Centrum voor Kinderoncologie B.V.

Contact name

Secretariat TDC

Locations

1 EU/EEA country · 1 investigational sites

By country

Investigational sites

Country notifications

Trial-start, recruitment-start, end and early-termination notifications submitted per Member State

Application history

3 submissions — initial application plus substantial / non-substantial modifications