Clinical trial NCT06551909: Radioimmunotherapy in Solid Tumors (PNRR-MCNT2-2023-12378239-Aim2)
Official title: Radioimmunotherapy in Solid Tumors (Aim 2- Stereotactic Neoadjuvant Radiotherapy for Glioblastoma)
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: NA
Conditions: Glioblastoma
Keywords: Glioblastoma
Neodjuvant Radiotherapy
Ultrahypofractionated Radiotherapy
Stereotactic Radiotherapy (SRT)
Simultaneous Integrated Boost (SIB)
Image Guidance
Lead sponsor: IRCCS San Raffaele
Sponsor class: OTHER
Collaborators: name: European Commission
name: Istituto Nazionale Tumori IRCCS - Fondazione G. Pascale
name: Azienda Ospedaliera di Rilievo Nazionale e di Alta Specialità San Giuseppe Moscati (Avellino)
First posted: 2024-08-13
Enrollment: 30
Sex: ALL
Minimum age (years): 18
Maximum age (years): 80
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: yes
Allocation: NA
Intervention model: SINGLE_GROUP
Intervention model description: This is study of feasibility in terms of toxicity of a dose escalation radiotherapy procedure, with 5 patients at each dose level, on 30 patients. The dose will be increased, moving to the next 5 patients, if no more than 1 acute toxicity of grade (G) 4 will be registered.

The assumption is that the percentage of patients free from cumulative acute toxicity G≥3 (Common Terminology Criteria of Adverse Events-CTCAE- v5.0 scale) at 1 month after the end of treatment should not exceed 30%. A sample size of 30 patients results in a two-sided 95% confidence interval with a width of 0.328 (0.136-0.464) when the sample proportion is 0.300.

Dropouts will be replaced by patients visited later, so as to reach the expected sample. Serum from 30 healthy volunteers, with sex and age characteristics comparable to the patients, will be collected to compare the level of immune biomarkers.
Primary purpose: TREATMENT

Brief summary: This is a prospective multicenter study of hypofractionated radiotherapy for the radiation treatment (RT) of solid tumors and in particular for Glioblastoma (in Aim 2). It is based on the results of ongoing studies at our Institute to validate the efficacy of extremely hypofractionated RT in neoadjuvant settings, which observed immunostimulatory effects of RT and the synergy with immune components. The collaboration between San Raffaele Hospital (Milan), the IRCCS Istituto Nazionale dei Tumori Fondazione G. Pascale (Naples) and the San Giuseppe Moscati Hospital of National Relief and High Specialty (Avellino) will ensure that patient recruitment, treatment and monitoring can be translated into facilities of the National Health System using common procedures. The various departments involved will treat patients with the same methods synergistically exploring the immuno/biological factors related to efficacy (and/or toxicity), based on new radioimmunotherapeutic approaches. Clinical and research activity will be developed jointly, drawing on the expertise in radiotherapy, radiomics, oncology, imaging and immunotherapy skills already available.

Detailed description: This is a prospective multicenter pilot study. Functional and spectroscopic neuroradiological imaging will be adopted for treatment planning. Specialized software will be used to perform radiomic feature extraction and analysis of pre-trained neural networks from the advanced MRI (magnetic resonance imaging) and CT (computed tomography) used for simulation, to identify distribution patterns of aggressive and radioresistant disease areas, with higher probability of disease recurrence, and to intensify the dose on the areas identified as more aggressive, in order to counteract intrinsic radioresistance. The hypofractionated radiotherapy paradigm claims the benefit of reduced treatment times, improved quality of life, better access to specialized treatment centers and potentially improved tumor outcomes with greater disease control and less tumor repopulation. The rationale for neoadjuvant RT is based on the idea of counteracting the tumor's aggressive mechanisms with radiotherapy before the disease is surgically removed, in order to maximize the immunostimulatory potential of RT, and therefore reduce recurrences. Neoadjuvant treatment offers numerous advantages, first of all the ability to adjust the dose to the pathological volume identified by MRI and limit the volume of irradiated healthy brain tissue. Furthermore, the use of imaging derived from functional neuroradiological and spectroscopic techniques for treatment planning would allow us to increase the dose on the areas identified as more aggressive, in order act against intrinsic radioresistance. One of the major risks could be the possibility of developing radionecrosis, but this would not be a cause for concern in the neoadjuvant setting, as all irradiated tissue will then be surgically removed. Patients who agree to participate in the study and who would be candidates for radical surgical treatment, according to the evaluation of the Neurosurgery Department of our Institute, will be treated. These patients will receive neoadjuvant radiation treatment in 5 fractions delivering 30 Gy on PTV and 35-50 Gy on GTV, with a dose-escalation modality that involves increasing the dose to 35-40-42.5-45-47.5-50 Gy in groups of 5 consecutive patients, using standard chemotherapy (TMZ) after surgery.

Current diagnostic brain MRI allows a good definition of the initial disease and its most aggressive areas. Since relapses have always been found to occur in irradiated areas and recent studies have shown that reducing margins does not affect overall survival, smaller margins will be used from GTV to CTV and from CTV to PTV. Therefore, smaller volumes will be generated and treated with hypofractionation. Biological equivalent doses (BED) to the standard prescription will be delivered, with boost to a higher biological equivalent dose, in the most aggressive areas, in order to obtain better local control, maintaining an acceptable level of toxicity and therefore improve the evolution of the disease. CE marked devices (software) will be used according to the approved use, for the definition of the target (CT and MRI) and for the delivery of the treatment (linear accelerators) and the standard drug, which has the authorization for marketing, will be prescribed. Radiomic features related to local response and survival will be identified, to obtain a predictive model. At the same time, we will collect PMBC and patient serum in the biobank to identify presumed immunocorrelated of therapy efficacy and/or predictive biomarkers of response/toxicity to therapy. For comparative purposes, serum from healthy volunteers will also be collected, in numbers equivalent to patients and with sex and age characteristics comparable to the latter.

Eligibility criteria: Inclusion Criteria:

* Diagnosis of Glioblastoma.
* ECOG performance score 0-2 (defined during the first visit)
* Surgically removable lesion (according to the operability criteria established by the Neurosurgery Unit)

For healthy volunteers, people who are as comparable as possible with the patient population in terms of sex and age will be recruited

Exclusion Criteria:

* Previous stroke
* Presence of another primary and/or metastatic tumor For healthy volunteers also, absence of primary and/or metastatic tumor

Primary outcomes:
measure: Acute toxicity
timeFrame: one month
Secondary outcomes:
measure: Disease Free Survival
timeFrame: From the date of radiotherapy end until the date of first documented clinical progression or date of death from any cause, whichever came first, assessed up to 36 months]
measure: Cancer Specific Survival
timeFrame: From the date of radiotherapy end until the date of first documented clinical progression or date of death from any cause, whichever came first, assessed up to 36 months]
measure: Overall survival
timeFrame: From the date of radiotherapy end until the date of death from any cause, assessed up to 36 months
measure: Local Relapse Free Survival
timeFrame: From the date of radiotherapy end until the date of local progression or date of death from any cause, whichever came first, assessed up to 36 months
measure: Intracranial Relapse Free Survival
timeFrame: From the date of radiotherapy end until the date of local progression or date of death from any cause, whichever came first, assessed up to 36 months
measure: Extracranial Relapse Free Survival
timeFrame: From the date of radiotherapy end until the date of local progression or date of death from any cause, whichever came first, assessed up to 36 months
measure: Late toxicity
timeFrame: From three months after the start of radiotherapy until the end of follow-up or death, assessed up to 36 months
measure: Subacute Toxicity
timeFrame: From one up to three months after the start of radiotherapy
measure: Incidence of Treatment-Emergent Adverse Events as assessed with brain tumor specific quality of life questionnaires
timeFrame: 36 months
measure: Incidence of Treatment-Emergent Adverse Events as assessed with functional-social- emotional and general well being questionnaires
timeFrame: 36 months
measure: Incidence of Treatment-Emergent Adverse Events as assessed with mental status questionnaires
timeFrame: 36 months
measure: Periferic mononuclear blood cells (PMBC) subtypes predictive for disease progression and death
timeFrame: Form the start of radiotherapy up to 6 months
Other outcomes:
measure: Radiomics
timeFrame: 36 months
measure: Predictive factors for disease progression and death
timeFrame: From radiotherapy end to date of local, regional progression, distant failure, or death, assessed up to 36 months
Locations:
city: Milan
country: Italy
facility: IRCCS San Raffaele Scientific Institute
state: MI
Study officials:
affiliation: IRCCS San Raffaele Scientific Institute
name: Nadia G Di Muzio, Prof
role: PRINCIPAL_INVESTIGATOR
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