Radioimmunotherapy in Solid Tumors (PNRR-MCNT2-2023-12378239-Aim2)

June 6, 2025 updated by: Nadia Di Muzio, IRCCS San Raffaele

Radioimmunotherapy in Solid Tumors (Aim 2- Stereotactic Neoadjuvant Radiotherapy for Glioblastoma)

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.

Study Overview

Status

Recruiting

Conditions

Intervention / Treatment

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.

Study Type

Interventional

Enrollment (Estimated)

30

Phase

  • Not Applicable

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Contact

Study Contact Backup

Study Locations

  • Italy
    • MI
      • Milan, MI, Italy, 20132
        • Recruiting
        • IRCCS San Raffaele Scientific Institute
        • Contact:
        • Contact:

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

  • Adult
  • Older Adult

Accepts Healthy Volunteers

Yes

Description

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

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Treatment
  • Allocation: N/A
  • Interventional Model: Single Group Assignment
  • Masking: None (Open Label)

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Experimental: Treatment arm
The 30 patients will receive neoadjuvant stereotactic radiotherapy in 5 fractions delivering 30 GY to PTV and 35-50 GY with Simultaneous Integrated Boost (SIB) to GTV using standard chemotherapy (TMZ) after surgery. GTV will be treated with escalating dose levels from 35 to 50 Gy. Patients will be divided into groups of 5 and will receive in the absence of 2 G4 toxicities per group, the following dose levels: 35-40-42.5-45-47.5 and 50 Gy
Radiation: Neoaddjuvant Stereotactic Radiotherapy with Simultaneous Integrated Boost
Patients with Glioblastoma will receive neoadjuvant stereotactic radiotherapy to Planning Target Volume (PTV) to 30 Gy in 5 fractions, and a Simultaneous Integrated Boost delivering 35-50 GY to GTV. Patients will be divided into groups of 5 and will receive (in the absence of 2 G4 toxicities per group), the following dose levels: 35-40-42.5-45-47.5 and 50 Gy. Standard Temozolomide chemotherapy will be prescribed after surgery.
Other Names:
  • Ultrahypofractionated Radiotherapy

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Acute toxicity
Time Frame: one month
Incidence of acute toxicity of grade 3 or 4 as maximum toxicity value during the radiation treatment or in any case within a month of the end of SBRT, using Common Terminology Criteria for Adverse Events (CTCAE) version 5.0 scale (toxicity from 0- patients without toxicity to 5-death from toxicity)
one month

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Disease Free Survival
Time Frame: 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]
Absence of disease progression during the follow-up
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]
Cancer Specific Survival
Time Frame: 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]
Death from disease progression during the follow-up
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]
Overall survival
Time Frame: From the date of radiotherapy end until the date of death from any cause, assessed up to 36 months
Survival from all causes
From the date of radiotherapy end until the date of death from any cause, assessed up to 36 months
Local Relapse Free Survival
Time Frame: 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
Local control of the disease (at the treated site)
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
Intracranial Relapse Free Survival
Time Frame: 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
Intracranial control of the disease (glioblastoma recurrence outside the treatment field)
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
Extracranial Relapse Free Survival
Time Frame: 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
Distant metastases
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
Late toxicity
Time Frame: From three months after the start of radiotherapy until the end of follow-up or death, assessed up to 36 months
Toxicity developed after three months until the end of follow-up or death, assessed with Common Terminology Criteria for Adverse Events (CTCAE) v5.0 scale, assessed with Common Terminology Criteria for Adverse Events (CTCAE) v5.0 scale, which displayes grades from 1 to 5, with grade 1 meaning mild toxicity and grade 5 death related to toxicity
From three months after the start of radiotherapy until the end of follow-up or death, assessed up to 36 months
Subacute Toxicity
Time Frame: From one up to three months after the start of radiotherapy
Incidence of acute toxicity of grade 3 or 4 as maximum toxicity value registered from one to three months of the end of SBRT, using Common Terminology Criteria for Adverse Events (CTCAE) version 5.0 scale (toxicity from 0- patients without toxicity to 5-death from toxicity)
From one up to three months after the start of radiotherapy
Incidence of Treatment-Emergent Adverse Events as assessed with brain tumor specific quality of life questionnaires
Time Frame: 36 months
Survey with the questionnaire of European Organisation for Research and Treatment of Cancer (EORTC) Quality of life of brain tumor patients (EORTC QLQ BN20) which contains 25 questions on patients' quality of life with answers from 1, lowest grade, to 4, highest grade
36 months
Incidence of Treatment-Emergent Adverse Events as assessed with functional-social- emotional and general well being questionnaires
Time Frame: 36 months
Survey with the questionnaire FACT-Br on patients' quality of life with answers from 0, lowest grade, to 4, highest grade
36 months
Incidence of Treatment-Emergent Adverse Events as assessed with mental status questionnaires
Time Frame: 36 months
Survey with the questionnaire Mini Mental Status Examination (MMSE). A score of 24-30 indicates normal abilities, while a lower score indicates cognitive deficit.
36 months
Periferic mononuclear blood cells (PMBC) subtypes predictive for disease progression and death
Time Frame: Form the start of radiotherapy up to 6 months
Identification of immune prognostic factors, studying lymphocyte subpopulations and their impact on the results obtained.
Form the start of radiotherapy up to 6 months

Other Outcome Measures

Outcome Measure
Measure Description
Time Frame
Radiomics
Time Frame: 36 months
Evaluation of radiomic characteristics: Mathematical extraction of the spatial distribution of signal intensities and pixel interrelationships of medical images of the patients, to quantify textural information resampled according to International Biomarker Standardization Initiative (IBSI).
36 months
Predictive factors for disease progression and death
Time Frame: From radiotherapy end to date of local, regional progression, distant failure, or death, assessed up to 36 months
To identify potential risk factors, the association of clinical and radiation treatment factors with survival outcomes will be estimated using survival trees, univariate/multivariate Cox regression models
From radiotherapy end to date of local, regional progression, distant failure, or death, assessed up to 36 months

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

IRCCS San Raffaele

Collaborators

European Commission
Istituto Nazionale Tumori IRCCS - Fondazione G. Pascale
Azienda Ospedaliera di Rilievo Nazionale e di Alta Specialità San Giuseppe Moscati (Avellino)

Investigators

  • Principal Investigator: Nadia G Di Muzio, Prof, IRCCS San Raffaele Scientific Institute

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

August 31, 2024

Primary Completion (Estimated)

August 31, 2026

Study Completion (Estimated)

February 28, 2027

Study Registration Dates

First Submitted

August 12, 2024

First Submitted That Met QC Criteria

August 12, 2024

First Posted (Actual)

August 13, 2024

Study Record Updates

Last Update Posted (Actual)

June 8, 2025

Last Update Submitted That Met QC Criteria

June 6, 2025

Last Verified

June 1, 2025

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • PNRR-MCNT2-2023-12378239- Aim2

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

YES

IPD Plan Description

The data that support the findings of this study (anonymized individual participant data) are available on request from the corresponding author to researchers who provide a methodologically sound proposal. Requests made to the corresponding author will be evaluated by the Lombardy Territorial Ethics Committee

IPD Sharing Time Frame

for 2 years after the end of the study

IPD Sharing Access Criteria

request from the corresponding author approved by the Lombardy Territorial Ethics Committee

IPD Sharing Supporting Information Type

  • STUDY_PROTOCOL
  • SAP
  • ANALYTIC_CODE
  • CSR

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

No

Studies a U.S. FDA-regulated device product

No

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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