Immunotherapy and Carbon Ion Radiotherapy In Solid Cancers With Stable Disease

Study Overview
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Brief Summary
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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.

Detailed Description
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This is a multicenter, open label, non-randomized phase II clinical trial aiming to assess the feasibility and the clinical activity of adding CIRT to ICIs in cancer patients that have obtained a disease stability (SD) with pembrolizumab administered as per standard of care. At study entry, hypofractionated CIRT will be delivered to one measurable lesion previously untreated with local approaches.CIRT will be performed at Fondazione CNAO, Pavia

Official Title
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Immune Checkpoint Inhibitors and Carbon iON Radiotherapy In Solid Cancers With Stable Disease

Conditions
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Non Small Cell Lung Cancer, Head and Neck Squamous Cell Carcinoma, Melanoma, Urothelial Carcinoma

Intervention / Treatment
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* Radiation: Carbon Ion Therapy
* Drug: Immunotherapy (Pembrolizumab)


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: 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 Willing and able to comply with scheduled visits, treatment schedule, laboratory testing, and other requirements of the study Females and males, 18 years of age or older (no upper limit for age) Eastern Cooperative Oncology Group (ECOG) performance status ≤ 2 Subjects must have measurable disease by CT or MRI per RECIST 1.1 Exclusion Criteria: 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 Patients with high tumor burden defined as > 10 lesions and/or sum of diameters > 19 cm Patients with distant metastases only located in the CNS are excluded Any serious or uncontrolled medical disorder that, in the opinion of the investigator, may increase the risk associated with study participation or study drug administration, impair the ability of the subject to receive protocol therapy, or interfere with the interpretation of study results Patients with autoimmune diseases (ADs), including local and systemic collagen-vascular (CVD) and inflammatory bowel diseases (IBD) Previous RT, regardless of energy, on the metastatic site selected to be irradiated. Any immune-related CTCAE grade 4 adverse event, before study entry Any CTCAE grade ≥3 immune-related adverse event observed within 3 weeks prior to CIRT start Presence of metal prostheses or any other condition to prevent adequate imaging for identification of the target volume and calculation of the dose Loco-regional conditions not allowing hadron therapy (e.g. active infections in RT target region) Prisoners or subjects who are involuntarily incarcerated Subjects who are compulsorily detained for treatment of either a psychiatric or physical illness (e.g. infectious disease)

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Interventional Model Description: Patient with solid cancer (NSCLC, HNSCC, melanoma, urothelial carcinoma) and a stable disease will be enrolled in the study.
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Solid cancers with stable disease<br>Only 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. Patients diagnosed with NSCLC, HNSCC, melanoma and urothelial carcinoma will be eligible for the study. | Radiation: Carbon Ion Therapy<br>* After 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.<br>Drug: Immunotherapy (Pembrolizumab)<br>* Only 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.<br>* Other names: Pembrolizumab;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | At least 8 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | At least 8 weeks | 
| 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. | At least 8 weeks | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Hadrontherapy, CIRT, Immunotherapy, NSCLC, HNSCC, Melanoma, Urothelial