Clinical trial NCT05190172: PRO-GLIO: PROton Versus Photon Therapy in IDH-mutated Diffuse Grade II and III GLIOmas
Official title: PRO-GLIO: PROton Versus Photon Therapy in IDH-mutated Diffuse Grade II and III GLIOmas
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: NA
Conditions: Oligodendroglioma
Oligodendroglioma, Anaplastic
Diffuse Astrocytoma, IDH-Mutant
Keywords: proton therapy
radiotherapy
IDH-mutated diffuse grade II astrocytoma
IDH-mutated diffuse grade III astrocytoma
oligodendroglioma
Lead sponsor: Oslo University Hospital
Sponsor class: OTHER
Collaborators: name: Sahlgrenska University Hospital
name: The Skandion Clinic
name: University Hospital of North Norway
name: St. Olavs Hospital
name: Haukeland University Hospital
name: Lund University Hospital
name: Ôrebro University Hospital
name: Uppsala University Hospital
name: Karolinska University Hospital
name: University Hospital, Umeå
name: University Hospital, Linkoeping
name: Jönköping University Hospital
First posted: 2022-01-13
Enrollment: 225
Sex: ALL
Minimum age (years): 18
Maximum age (years): 65
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: * Experimental treatment arm with proton radiationtherapy
* Standard treatment arm with photon radiationtherapy
Primary purpose: TREATMENT

Brief summary: 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.

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.

Eligibility criteria: 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 (more than 1 or 2 punctate contrast enhancing foci) 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. Known CDKN2A/B homozygous deletion
4. Presence of any medical, psychological, familial, sociological, or geographical characteristic that might impair patient compliance for study protocol procedures including follow-up
5. Body weight \> 150 kg

Primary outcomes:
measure: First intervention free survival (FIFS) at 2 years
timeFrame: 2 years
Secondary outcomes:
measure: Total fatigue score assessed by the fatigue questionnaire developed by T. Chalder et al.
timeFrame: 2, 5, 10 and 15 years
measure: Change in cognitive functioning (composite score from CANTAB-tests) at 2 years
timeFrame: 5 months and 2, 5, 10 and 15 years
measure: Overall survival
timeFrame: Median and at 2, 5, 10 and 15 years
measure: FIFS
timeFrame: Median, 5, 10 and 15 years
measure: Progression-free survival
timeFrame: Median and at 2, 5, 10 and 15 years
measure: Change in neurological function as assessed by the NANO scale
timeFrame: 2, 5, 10 and 15 years
measure: Global cognitive impairment index
timeFrame: 2, 5, 10 and 15 years
measure: Rate of local, distant and combined recurrences
timeFrame: 2, 5, 10 and 15 years
measure: Rate of patients without epileptic seizures
timeFrame: 5 months and 2, 5, 10 and 15 years
measure: EORTC QLQ C30-based algorithm score
timeFrame: 2, 5, 10 and 15 years
measure: Incremental cost effectiveness ratio
timeFrame: 2, 5, 10 and 15 years
measure: Rate of adverse events
timeFrame: At 6 weeks, 3 and 5 months and 1 year, 2 , 5, 10 and 15 years
measure: Costs in Norwegian kroner related to loss of production caused by disease and treatment
timeFrame: 2, 5, 10 and 15 years
Other outcomes:
Locations:
city: Oslo
country: Norway
facility: Oslo University Hospital
Study officials:
affiliation: Head of Neurooncology
name: Petter Brandal, MD PhD
role: PRINCIPAL_INVESTIGATOR
References: