PNOC022: A Combination Therapy Trial using an Adaptive Platform Design for Children and Young Adults with Diffuse Midline Gliomas (DMGs) including Diffuse Intrinsic Pontine Gliomas (DIPGs) at Initial Diagnosis, Post-Radiation Therapy and at Time of Progression

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

20 Oct 2022 → ongoing

Decision date (initial)

2024-05-21

Transition trial

Yes

Low-intervention

No

Rare-disease indication

Yes

Vulnerable population

No

External identifiers

EU CT number

2023-507598-16-00

EudraCT number

2022-000636-40

ClinicalTrials.gov

NCT05009992

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Therapy, Pharmacodynamic, Safety, Pharmacokinetic, Efficacy

Cohorts 1 and 2
Maintenance Combinations:
• To assess efficacy of combination therapy with ONC201 and novel agent in participants with DMG based on median progression-free survival at 6 months (PFS6)
Cohort 3
• To assess efficacy of combination therapy with ONC201 and novel agent in participants with recurrent DMG based on overall survival at 7 months (OS7)

Conditions and MedDRA coding

Diffuse Midline Gliomas (DMGs) including Diffuse Intrinsic Pontine Gliomas (DIPGs)

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 16

1. Cohort 1A and 1B (participants with newly diagnosed DMG prior to radiation therapy): New diagnosis of DMG with imaging and/or pathology consistent with a DMG, including spinal cord tumors. In cohort 1B, previous tumor tissue confirmation of DMG is mandatory and pathology must be consistent with a DMG including diffuse midline glioma H3K27M mutant; WHO Grade 3 and 4 H3 wildtype gliomas.
2. Cohort 2A and 2B (participants with DMG who have completed radiation therapy): -Diagnosis of DMG with imaging and/or pathology consistent with a DMG, including spinal cord tumors, who have completed standard-of-care radiation therapy. In cohort 2B, previous tumor tissue confirmation of DMG is mandatory and pathology must be consistent with a DMG including diffuse midline glioma H3K27M mutant; WHO Grade 3 and 4 H3 wildtype gliomas.
3. Cohort 2A and 2B (participants with DMG who have completed radiation therapy): -Participants must be within 4-14 weeks of completion of radiation.
4. Cohort 3A and 3B (participants with DMG at progression): -Diagnosis of recurrent DMG with imaging and/or pathology consistent with a DMG, including spinal cord tumors, who have completed standard-of-care radiation therapy. In Cohort 3B, previous tumor tissue confirmation of DMG is mandatory and pathology must be consistent with a DMG including diffuse midline glioma H3K27M mutant; WHO Grade 3 and 4 H3 wildtype gliomas.
5. Cohort 3A and 3B (participants with DMG at progression): -Participants must have evidence of progression and not have received any treatment for this progression and have not previously received re-irradiation.
6. All Cohorts: -Age 2 to 39 years.
7. All Cohorts: Participants must have recovered from all acute side effects of prior therapy.
8. All cohorts: Participant body weight must be above the minimum necessary for the participant to receive ONC201 (at least 10 kg).
9. All cohorts: From the projected start of scheduled study treatment, the following time periods must have elapsed: At least 7 days after last dose of a biologic agent or beyond time during which adverse events are known to occur for a biologic agent, 5 half-lives from any investigational agent, 4 weeks from cytotoxic therapy (except 23 days for temozolomide and 6 weeks from nitrosoureas), 6 weeks from antibodies (21 days for bevacizumab when used for tumor-directed therapy, guidance on use for pseudoprogression is below), or 4 weeks (or 5 half-lives, whichever is shorter) from other anti-tumor therapies. o For participants who have received radiotherapy, participants in Cohort 2 must be between 4 and 14 weeks from the completion of local up-front radiotherapy and not have received additional therapy beyond completion of radiation therapy. o The use of bevacizumab to control radiation therapy-induced edema is allowed (if used for tumor-directed therapy, please see required time period above).  Dosing limitations are as follows: • Bevacizumab (or equivalent) for up to a maximum of 5 doses, dosing per institutional standard. There is no required washout period.
10. All cohorts: Prior use of temozolomide during radiation at maximum of the standard pediatric dosing (defined as 90 mg/m2 /dose continuously during radiation therapy for 42 days) or dexamethasone is allowed.
11. All cohorts: Corticosteroids: Participants who are receiving dexamethasone must be on a stable or decreasing dose for at least 3 days prior to baseline MRI scan.
12. All cohorts: The participant must have adequate organ function defined as: Adequate Bone Marrow Function Defined as: • Peripheral absolute neutrophil count (ANC) ≥ 1000/mm3 (1.0g/l) and • Platelet count ≥ 100,000/mm3 (100x109/l) (transfusion independent, defined as not receiving platelet transfusions for at least 7 days prior to enrollment). Adequate Renal Function Defined as: • Creatinine clearance or radioisotope GFR ≥ 70mL/min/1.73 m2 or • A serum creatinine within the normal limits for age. Adequate Liver Function Defined as: • Bilirubin (sum of conjugated + unconjugated) ≤ 1.5 x upper limit of normal (ULN) for age and • SGPT (ALT) ≤ 2x ULN and • Serum albumin ≥ 2 g/dL. Adequate Pulmonary Function Defined as: • No evidence of dyspnea at rest, no exercise intolerance due to pulmonary insufficiency, and a pulse oximetry of > 92% while breathing room air. Adequate Gastrointestinal Function Defined as: • Diarrhea < grade 2 by CTCAE v5.0. Adequate Metabolic Function Defined as: • Non-fasting glucose < 125 mg/dL without the use of antihyperglycemic agents. • If non-fasting glucose > 125 mg/dL, a fasting glucose should be done. If fasting glucose ≤ 160mg/dL without the use of antihyperglycemic agents, participant will meet adequate metabolic function criteria. • Triglycerides of < 300 mg/dl and total cholesterol of < 300 mg/dl – can be on lipid lowering medications as needed to achieve. Adequate Cardiac Function Defined as: • No history of congestive heart failure or family history of long QT syndrome. • ECG must be obtained to verify the QTC. If an abnormal reading is obtained, the ECG should be repeated in triplicate.  QTC <470 msec • Participants with history of congestive heart failure, at risk of having or have underlying cardiovascular disease, or with history of exposure to cardiotoxic drugs must have adequate cardiac function as determined by echocardiogram.  Shortening fraction of ≥27% by echocardiogram Adequate Neurologic Function Defined as: • Participants with seizure disorder may be enrolled if seizure disorder is well controlled.
13. All cohorts: The effects of the study drugs 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.
14. All cohorts: Karnofsky ≥ 50 for Participants> 16 years of age and Lansky ≥ 50 for participants ≤ 16 years of age (See Appendix A). 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.
15. All cohorts: 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. Participants who do not meet this criteria must be discussed with Study Chair(s).
16. All cohorts: 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 16

1. Cohort 1A and 1B (participants with newly diagnosed DMG prior to radiation therapy): • Prior exposure to radiation therapy. • Thalamic H3K27M DMG
2. Cohort 2A and 2B: For tumors that do not have a pontine or spinal cord epicenter the following specific exclusion criteria apply: o Thalamic H3K27M DMG that has undergone standard radiation without concurrent therapy (other than temozolomide)
3. Cohort 1A and 2A (participants with newly diagnosed DMG prior to radiation therapy and who have not previously undergone tumor tissue collection prior to study entry): • Deemed not appropriate for tissue resection/biopsy.
4. Cohort 3A and 3B (participants with DMG at progression): • Prior exposure to re-irradiation for tumor progression. • 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.
5. All cohorts: • Diagnosis of a histone H3 wildtype Grade 2 diffuse astrocytoma
6. All cohorts: • Investigational Drugs o Participants who are currently receiving another investigational drug. Investigational imaging agents or agents used to enhance tumor visibility on imaging or during tumor biopsy/resection should be discussed with the study chairs.
7. All cohorts: • Anti-cancer Agents o Participants who are currently receiving other anti-cancer agents.
8. All cohorts: • 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. 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.
9. All cohorts: • Participants with uncontrolled infection or other uncontrolled systemic illness.
10. All cohorts: • 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 (as clinically indicated).
11. All cohorts: • Active illicit drug use or diagnosis of alcoholism.
12. All cohorts: • History of allergic reactions attributed to compounds of similar chemical or biologic composition as the agents used in study.
13. All cohorts: • Evidence of disseminated disease, including multi-focal disease, diffuse leptomeningeal disease or evidence of CSF dissemination.
14. All cohorts: • Known additional malignancy that is progressing or requires active treatment within 3 years of start of study drug.
15. All cohorts: • Concomitant use of potent CYP3A4/5 inhibitors during the treatment phase of the study and within 72 hours prior to starting study drug administration.
16. All cohorts: • Concomitant use of potent CYP3A4/5 inducers, which include enzyme inducing antiepileptic drugs (EIAEDs; see Appendix I), during the treatment phase of the study and within 2 weeks prior to starting treatment. Concurrent corticosteroids is allowed.

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 2

1. The primary efficacy endpoint for both Cohorts 1 and 2 is progressionfree survival at 6 months (PFS6). PFS6 is defined as the percentage of participants alive and free from progression at 6 months (26 weeks) after the initiation of the combination of the ONC201 with a novel agent given in the maintenance phase of therapy.
2. The primary efficacy endpoint in Cohort 3 is overall survival at 7 months (OS7). OS7 is defined as the percentage of participants alive at 7 months (30 weeks) after the initiation of the combination of ONC201 with a novel agent given in the maintenance phase of therapy.

Investigational products

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

Test 2

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

Oversight and notifications

Regulatory notifications under CTR Articles 38, 52, 53, 54 and 77

Temporary halts 1 · Art. 38 CTR

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Documents 25 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

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