The ACTION Study: ONC201 in H3 K27M-mutant Diffuse Glioma Following Radiotherapy

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Chimerix Inc.

Participant type

Pediatric, Patients

Age range

0-17 years, 18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Neoplasms [C04]

Trial duration

28 Apr 2023 → ongoing

Decision date (initial)

2024-01-15

Transition trial

No

Low-intervention

No

Rare-disease indication

Yes

Vulnerable population

Yes

Funding sources

Chimerix, Inc, a Jazz Pharmaceuticals company

External identifiers

EU CT number

2022-502051-56-00

WHO UTN

U1111-1285-3702

ClinicalTrials.gov

NCT05580562

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Safety, Efficacy, Pharmacokinetic

To evaluate the efficacy of dordaviprone administered following radiotherapy in participants with H3 K27Mmutant diffuse glioma

Secondary objectives 4

1. To evaluate the efficacy of dordaviprone versus placebo administered following radiotherapy in participants with H3 K27M-mutant diffuse glioma
2. To evaluate the safety and tolerability of dordaviprone versus placebo
3. To evaluate clinical benefits of treatment with dordaviprone
4. To evaluate the impact of dordaviprone on health-related QoL and neurological function

Conditions and MedDRA coding

H3 K27M-mutant diffuse glioma

Study design 2 periods

Regulatory references

EMA paediatric investigation plan (PIP)

EMEA-003389-PIP01-23

Plan to share IPD

No

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 8

1. Able to understand the study procedures and agree to participate in the study by providing written informed consent (by participant or legally authorized representative), and assent when applicable.
2. Body weight ≥ 11 kg at time of randomization.
3. Histologically diagnosed H3 K27M-mutant diffuse glioma (new diagnosis). Detection of a missense K27M mutation in any histone H3-encoding gene detected by testing of tumor tissue (IHC or NGS in a CLIA-certified or equivalent laboratory). [Site to provide (as available): ≥ 11 unstained FFPE slides from tumor tissue.]
4. At least one, high-quality, contrast-enhanced MRI of the brain obtained prior to starting radiotherapy for submission to sponsor’s imaging vendor for central read. For participants who had a surgical resection, this scan must be post-resection; for participants who did not have a resection, this scan may be pre- or post-biopsy.
5. At least one, high-quality, contrast-enhanced MRI of the brain obtained 2 to 6 weeks after completion of frontline radiotherapy. [Site to also provide all available MRIs completed prior to initiating treatment with study intervention.]
6. Received standard frontline radiotherapy within 2 to 6 weeks prior to randomization. Standard frontline radiotherapy is defined as a dose of 54 to 60 Gy at 1.8 to 2.2 Gy/fraction. Radiotherapy must be initiated within 12 weeks from initial diagnosis of H3 K27M-mutant diffuse glioma and within 8 weeks of most recent surgical resection/biopsy.
7. Karnofsky Performance Status or Lansky Performance Status ≥ 70 at time of randomization.
8. Stable or decreasing dose of corticosteroids and anti-seizure medications for 7 days prior to randomization, if applicable. Stable steroid dose is defined as ≤2 mg/day increase (based on dexamethasone dose or equivalent dose of an alternative steroid).

Exclusion criteria 14

1. 1. Primary spinal tumor
2. 2. Diffuse intrinsic pontine glioma (DIPG), defined as tumors with a pontine epicenter and diffuse involvement of the pons.
3. 3. Evidence of leptomeningeal spread of disease or cerebrospinal fluid dissemination.
4. 4. Any known concurrent malignancy.
5. 5. New lesion(s) outside of the radiation field.
6. 6. Received whole-brain radiotherapy.
7. 7. Received proton therapy for glioma.
8. 8. Use of any of the following treatments within the specified time periods prior to randomization: a. Dordaviprone (ONC201) or ONC206 at any time; b. bevacizumab (includes biosimilars) at any time; c. Temozolomide within past 3 weeks; d. Tumor treating fields at any time; e. DRD2 antagonist within past 2 weeks; f. Any investigational therapy within past 4 weeks; g. Strong CYP3A4/5 inhibitors within 3 days; h. Strong CYP3A4/5 inducers (includes enzyme-inducing antiepileptic drugs) within 2 weeks.
9. 9. Laboratory test results meeting any of the following parameters within 2 weeks prior to randomization: a. Absolute neutrophil count <1.0 × 10^9/L or platelets <75 × 10^9/L; b. Total bilirubin >1.5 × upper limit of normal (ULN) (participants with Gilbert’s syndrome may be included with total bilirubin >1.5 × ULN if direct bilirubin is ≤1.5 × ULN); c. Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) >2.5 × ULN; d. Creatinine clearance ≤60 mL/min as calculated by the Cockcroft Gault equation (or estimated glomerular filtration rate <60 mL/min/1.73 m2).
10. 10. QTc > 480 msec (based on mean from triplicate electrocardiograms) during screening.
11. 11. Known hypersensitivity to any excipients used in the study intervention formulation.
12. 12. Pregnant, breastfeeding, or planning to become pregnant while receiving study intervention or within 3 months after the last dose. Participants of childbearing potential must have a negative serum pregnancy test within 72 hours prior to receiving the first dose of study intervention.
13. 13. Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection requiring systemic therapy or psychiatric illness/social situations that would limit compliance with study requirements.
14. 14. Any other condition (eg, medical, psychiatric, or social) that, in the opinion of the investigator, may interfere with participant safety or the ability to complete the study according to the protocol.

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 1

1. Overall survival

Secondary endpoints 5

1. • Incidence of AEs: overall, treatment-related, Grade 3 or higher in severity, serious, fatal, those resulting in treatment discontinuation, and events of special interest • Change from baseline in clinical laboratory parameters • Distribution of graded clinical laboratory parameters
2. • PFS using RANO 2.0 criteria for all participants * PFS using RANO-HGG criteria for participants with measurable contrast-enhancing disease
3. • Corticosteroid response • Time to first corticosteroid response • Duration of first corticosteroid response • Cumulative duration of corticosteroid responses • Corticosteroid dose and change from baseline over time • Time to corticosteroid use deterioration
4. • Performance status response • Time to first performance status response • Duration of first performance status response • Cumulative duration of performance status responses • Performance status and change from baseline over time • Time to performance status deterioration
5. • Change from baseline in QoL assessments o ≥ 18 years of age: EORTC-QLQ-C30, QLQ-BN20, and MDASI-BT o 2 to < 18 years of age: PedsQL Brain Tumor Module • Change from baseline in Neurologic Assessment in Neuro-Oncology (NANO) score

Investigational products

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

Test 1

Placebo 1

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Chimerix Inc.

Sponsor organisation

Chimerix Inc.

Address

2505 Meridian Parkway Suite 340

City

Durham

Postcode

27713-5247

Country

United States

Scientific contact point

Organisation

Chimerix Inc.

Contact name

ONC- Clinical Trial Manager

Public contact point

Organisation

Chimerix Inc.

Contact name

ONC- Clinical Trial Manager

Third parties 14

Locations

6 EU/EEA countries · 36 investigational sites

By country

Investigational sites

Country notifications

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

Results and documents

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

Documents 156 files

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

Application history

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