PRO-GLIO: PROton Versus Photon Therapy in IDH-mutated Diffuse Grade II and III GLIOmas (PRO-GLIO)

Proton therapy is a powerful tool enabling oncologists to spare normal tissue around the target for irradiation much better than what can be achieved with photon irradiation. The infiltrative nature of IDH-mutated grade II and III diffuse glioma, however, renders proton therapy a potential problem. A randomized controlled trial (RCT) is the only option when trying to ensure that chances of long-term survival are not impaired seeking to reduce unwanted late treatment effects. Non-inferiority of proton therapy compared to photon irradiation is the primary endpoint of the RCT.

Hence, PRO-GLIO has two main objectives. First, PRO-GLIO will evaluate if proton therapy is safe in patients with IDH-mutated grade II and III diffuse glioma, showing that survival figures at 2 years from radiotherapy are not poorer in the proton arm than in the photon arm. Second, we want to find the true number of patients in need of rehabilitation in both arms, and evaluate if proton therapy conveys a higher QoL than photon irradiation at 2 years from radiotherapy.

Study Overview

• Status: Recruiting
• Conditions: Oligodendroglioma; Oligodendroglioma, Anaplastic; Diffuse Astrocytoma, IDH-Mutant
• Intervention / Treatment: Radiation: Radiation therapy

Detailed Description

PRO-GLIO aims at establishing proton irradiation as standard radiotherapy for IDH-positive diffuse glioma grade II and III patients. First, PRO-GLIO will show that proton therapy is safe, despite the infiltrative nature of these tumors. Second, the HRQOL and neuropsychological investigating part of PRO-GLIO will show that patients irradiated with protons have a better outcome in this regard than those irradiated with photons. Inclusion criteria are a diagnosis of grade II or grade III IDH-mutated diffuse glioma, good performance status, indication for radiotherapy and age between 18 and 65 years.

Patients will be randomized to proton or photon radiotherapy and the study work will be divided in three work packages (WP).

1. In WP1, survival data will be the main focus, but the estimation of QALY will also be an important part - concentrating on differences between the two study arms. If there is truly no difference between the proton and photon radiotherapy on the probability of FIFS after two years, then 224 randomized patients (112 in each treatment group) are required to be 80% certain that the upper limit of a two-sided 95% confidence interval will exclude a difference in favor of the photon radiotherapy of more than 15%. This assumes a 0.8 probability of FIFS in the control arm, and no drop-outs.
2. In WP2, a battery of validated neuropsychological tests will be used to test the cognive abilities of the patients. All patients will be testes using an internet-based test (Cog-State) and 1/3 of patients will also have an in-depth neuropsychological evaluation. The two methods will be compared.
3. In WP3, a battery of patient-reported outcome measures (PROMS) questionnaires will be used to establish which subjective challenges this patient group struggles the most with.

• Study Type: Interventional
• Enrollment (Estimated): 225
• Phase: Not Applicable

Contacts and Locations

• Study Contact: Name: Petter Brandal, MD PhD; Phone Number: +47 22934000; Email: petter.brandal@ous-hf.no
• Study Contact Backup: Name: Carin Granlund; Phone Number: +4722934000; Email: carvan@ous-hf.no

Study Locations

• Norway
  • Oslo, Norway
    • Recruiting
    • Oslo University Hospital
    • Contact: Petter Brandal, MD Phd; Phone Number: +47 22935843; Email: pebra@ous-hf.no

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 65 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

1. Patients must be 18 to 65 years old at the day of consenting
2. IDH-mutated astrocytoma grade II or III, or oligodendroglioma grade II or III according to WHO 2016
3. Indication for radiotherapy
4. WHO/ECOG performance status 0-2
5. Ability to undergo MRI
6. No significant contrast enhancing tumor at the time of randomization. In recurrence patients, no contrast enhancement is allowed unless a new biopsy confirms the diagnosis of IDH-mutated astrocytoma grade 2 or 3, or oligodendroglioma grade 2 or 3.
7. Ability and willingness to travel to The Skandion Clinic for proton therapy if randomized to the proton therapy arm
8. Women of child-bearing potential (WOCBP) must agree to use an effective method of contraception during radiotherapy, chemotherapy and 1 year after completion of chemotherapy. Pregnancy is not an ineligibility criterium if radiotherapy is indicated and cannot be postponed
9. Ability to understand the information about the study and included treatment and give a written informed consent
10. Signed informed consent
11. Ability to speak and understand Norwegian or Swedish language

Exclusion Criteria:

1. Prior treatment (except surgery) for diffuse glioma
2. Concomitant or previous malignancies. Exceptions are adequately treated basal cell carcinoma or squamous cell carcinoma of the skin, or in situ carcinoma of the cervix uteri with a follow-up time of at least 3 years, or other previous malignancy with a disease-free interval of at least 5 years
3. More than 2 months from randomization to start radiotherapy
4. Known CDKN2A/B homozygous deletion
5. Presence of any medical, psychological, familial, sociological, or geographical characteristic that might impair patient compliance for study protocol procedures including follow-up
6. Body weight > 150 kg

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Radiation therapy with protons; Radiation therapy with protons at The Skandion Clinic, Uppsala, Sweden	Radiation: Radiation therapy; Radiation therapy either with protons or photons
Active Comparator: Radiation therapy with photons; Radiation therapy with photons at an University Hospital nearby subject's home address	Radiation: Radiation therapy; Radiation therapy either with protons or photons

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
First intervention free survival (FIFS) at 2 years	Survival	2 years

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Total fatigue score assessed by the fatigue questionnaire developed by T. Chalder et al.	Symptom	2, 5, 10 and 15 years
Overall survival	Survival	Median and at 2, 5, 10 and 15 years
Change in neurological function as assessed by the NANO scale	Objective examination	2, 5, 10 and 15 years
Global cognitive impairment index	Neuropsychological endpoint	2, 5, 10 and 15 years
Rate of local, distant and combined recurrences	Disease development	2, 5, 10 and 15 years
Rate of patients without epileptic seizures	Symptom	5 months and 2, 5, 10 and 15 years
EORTC QLQ C30-based algorithm score	Quality of life	2, 5, 10 and 15 years
Incremental cost effectiveness ratio	Health economics	2, 5, 10 and 15 years
Rate of adverse events	Toxicity	At 6 weeks, 3 and 5 months and 1 year, 2 , 5, 10 and 15 years
Costs in Norwegian kroner related to loss of production caused by disease and treatment	Health economics	2, 5, 10 and 15 years
Change in cognitive functioning (composite score from CANTAB-tests) at 2 years	Objective examination	5 months and 2, 5, 10 and 15 years
FIFS	Survival	Median, 5, 10 and 15 years
Progression-free survival	Survival	Median and at 2, 5, 10 and 15 years

Collaborators and Investigators

• Sponsor: Oslo University Hospital
• Collaborators: Karolinska University Hospital; University Hospital of North Norway; Sahlgrenska University Hospital, Sweden; Haukeland University Hospital; St. Olavs Hospital; University Hospital, Linkoeping; Lund University Hospital; University Hospital, Umeå; Uppsala University Hospital; Ôrebro University Hospital; The Skandion Clinic
• Investigators: Principal Investigator: Petter Brandal, MD PhD, Head of Neurooncology

Study record dates

Study Major Dates

• Study Start (Actual): January 14, 2022
• Primary Completion (Estimated): December 31, 2025
• Study Completion (Estimated): December 31, 2041

Study Registration Dates

• First Submitted: July 15, 2021
• First Submitted That Met QC Criteria: January 12, 2022
• First Posted (Actual): January 13, 2022

Study Record Updates

• Last Update Posted (Actual): April 3, 2024
• Last Update Submitted That Met QC Criteria: April 1, 2024
• Last Verified: April 1, 2024

More Information

Terms related to this study

• Keywords: radiotherapy; oligodendroglioma; proton therapy; IDH-mutated diffuse grade II astrocytoma; IDH-mutated diffuse grade III astrocytoma
• Additional Relevant MeSH Terms: Neoplasms by Histologic Type; Neoplasms; Neoplasms, Glandular and Epithelial; Glioma; Neoplasms, Neuroepithelial; Neuroectodermal Tumors; Neoplasms, Germ Cell and Embryonal; Neoplasms, Nerve Tissue; Astrocytoma; Oligodendroglioma
• Other Study ID Numbers: 265626

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: In accordance with Norwegian Data Protection Law, the dataset is only available by physical appearance at Oslo University Hospital, Norway upon request. To access data, please contact principal investigator Petter Brandal (petter.brandal@ous-hf.no). Data will not be shared before planned analyses are performed and published. The study protocol is also available upon request.
• IPD Sharing Time Frame: Data will be available following publication of the primary and key secondary endpoints. The study protocol is available upon request from this date
• IPD Sharing Access Criteria: Physical appearance at Oslo University Hospital, Norway.
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL; SAP

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No