Immunotherapy has become the standard of care in different advanced malignancies. Its effectiveness in the palliative setting was demonstrated by several phase III trials. However, the response rate varies according to the cancer under study and to the line of treatment. A potential way to improve the activity of single agent immune checkpoint inhibitors (ICIs) is to enhance the clinical response through further antitumor agents, including radiotherapy. Studies showed that carbon ions may lead to a broader immunogenic response; for their dosimetric characteristics it is possible to reduce integral dose sparing immune cells to direct and sustain a tumor specific immune response.
Considering the available preclinical and clinical evidence together, the goal of this study is to explore the feasibility and the clinical activity of adding carbon ion radiotherapy (CIRT), employed with a fractionation strategy comparable to stereotactic body radiation, to ICIs in advanced malignancies where immunotherapy is currently the standard of care.
Signed written informed consent
Histologic confirmation of malignancies under treatment with single agent anti-PD1/PDL1 immunotherapy per clinical practice (see cohort specific inclusion criteria) with immune checkpoint inhibitors approved by Italian national drug regulatory agencies (Agenzia Italiana del Farmaco, AIFA)
Having a disease stability as assessed by AIFA monitoring sheet
Presence of at least 2 measurable target lesions, of which at least one to be followed up as per RECIST and one suitable for CIRT
Patients treated with chemo-immunotherapy associations
Patients treated with immunotherapy combinations (e.g. subjects treated with anti-CTLA4 + anti-PD1/PDL1 are excluded)
Patients receiving immunotherapy within clinical trials
Patients receiving off-label immunotherapy or within expanded access programs or as compassionate use
Single group
Carbon Ion Therapy
RadiationAfter confirming the disease stability and upon patient inclusion in the study, hypofractionated carbon ion boost will be administered to one site of disease previously untreated. Patient will be irradiated to a single lesion with a total dose of 24 Gy\[RBE\], 8 Gy\[RBE\]/fraction, one fraction/day, for 3 days.
Immunotherapy (Pembrolizumab)
DrugOnly cancer patients under treatment with pembrolizumab monotherapy, administered within clinical practice and according to the Italian Drug Regulatory Agency (Agenzia Italiana del Farmaco, AIFA), will be enrolled.
Objective response rate assessed by RECIST V1.1
To estimate the effect, in terms of clinical response, of immunotherapy associating carbon ion treatment (CIRT) in the palliative setting across different malignancies, for which immunotherapy is currently the standard of care. Objective response rate (ORR) will be evaluated after CIRT administrated during immunotherapy maintenance in patients with stable disease. ORR will be assessed in the whole population according to RECIST v1.1. The proportion of ORR will be estimated within each disease.
Treatment-related adverse events assessed by CTCAE V5.0
To describe the safety profile of the association of carbon ion radiation therapy and systemic immunotherapy in the palliative setting across different malignancies, for which immunotherapy is currently the standard of care. Treatment-related adverse events will be evaluated according to CTCAE version 5.0.
Efficacy in terms of survival
To estimate the effect, in terms of survival, of immunotherapy with the association of carbon ion radiation treatment in the palliative setting across different malignancies, for which immunotherapy is currently the standard of care. Progression-Free Survival (PFS) will be calculated as the time between the start date of immunotherapy associated with carbon ion and the progression of disease, or death or last-follow-up. PFS will be estimated, within each malignancy, by Kaplan-Meier product limit method. Overall survival (OS) will be calculated as the time between the start date of immunotherapy associated with carbon ion and the death for any cause or last follow-up. OS will be estimated, within each malignancy, by Kaplan-Meier product limit method.
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CNAO National Center of Oncological Hadrontherapy
Lead sponsor
Fondazione IRCCS Istituto Nazionale dei Tumori, Milano, Italy
Collaborator
Fondazione IRCCS Policlinico San Matteo, Pavia, Italy
Collaborator
GSI Helmholtzzentrum für Schwerionenforschung GmbH, Darmstadt, Germany
Collaborator
