Investigation of the Timely-coordinated Therapy of Patients With Metastatic Cancer by Radiotherapy Together With Immune Checkpoint Inhibition

Study Overview
=================
Brief Summary
-----------------
Immunotherapy for the treatment of several cancer entities steadily increased during the last years. The data from the finalized and ongoing studies show the tremendous impact of immune checkpoint inhibition (ICI) also for advanced metastatic patients. Especially the ICI with pembrolizumab and nivolumab have an increasing number of first line treatment approvals. However, in particular metastatic patients which receive ICI therapy are often irradiated for immediate palliation of several metastases. Preclinical work revealed that radiotherapy (RT) is capable to modulate the tumor phenotype, its microenvironment in a way that systemic anti-tumor immune responses are induced. However, radiation has also immune suppressive properties as e.g. the expression of immune checkpoint molecules is increased following radiotherapy. So the ICI therapy in combination with the RT has the potential to overcome the immunotolerance of the tumor and the metastases. More and more reports therefore describe a so-called systemic immune-modulating effect of radiotherapy (former and still often named as abscopal effect). However the timely application of ICI and RT is often randomly and depends on the clinical need for the palliative RT. The aim of this trial is therefore to standardize the chronology of RT in combination with ICI, to evaluate the effects of radio-immunotherapy with a stratified and comparable patient cohort. The ST-ICI study is a prospective and observational study not influencing the standard therapeutic scheme and will provide hints how the radio-immune therapy drives systemic anti tumor responses.

Official Title
-----------------
Investigation of the Timely-coordinated Therapy of Patients With Metastatic Cancer by Radiotherapy Together With Immune Checkpoint Inhibition

Conditions
-----------------
Metastatic Cancer

Intervention / Treatment
-----------------
* Drug: Nivolumab
* Drug: Pembrolizumab
* Radiation: Radiotherapy
* Drug: Ipilimumab


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Patients suffering and diagnosed for: metastatic cancer of several entities Clinical indicated therapy with PD-1/PD-L1 inhibitors or CTLA-4 antagonists Optionally radiotherapy if clinically indicated Age at least 18 years Exclusion Criteria: fertile patients who refuse effective contraception during study treatment persistent drug and/or alcohol abuse patients not able or willing to behave according to study protocol patients in care patients that are not able to speak German patients which are imprisoned according to legal or governmental order

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| anti CTLA-4<br>The study cohort consist of patients suffering from metastatic cancer of several entities which will be treated with palliative RT and/or ICI (anti CTLA-4) at Department of Radiation Oncology of Universitätsklinikum Erlangen. | Radiation: Radiotherapy<br>* The normal clinical treatment-plan of the underlying disease remains unchanged.<br>Drug: Ipilimumab<br>* The normal clinical treatment-plan of the underlying disease remains unchanged.<br>|
| anti PD-1/PD-L1<br>The study cohort consist of patients suffering from metastatic cancer of several entities which will be treated with palliative RT and/or ICI (anti PD-1/PD-L1) at Department of Radiation Oncology of Universitätsklinikum Erlangen. | Drug: Nivolumab<br>* The normal clinical treatment-plan of the underlying disease remains unchanged.<br>Drug: Pembrolizumab<br>* The normal clinical treatment-plan of the underlying disease remains unchanged.<br>Radiation: Radiotherapy<br>* The normal clinical treatment-plan of the underlying disease remains unchanged.<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Systemic (according to iRECIST criteria) and local response of detected metastases during radio and/or immunotherapy. |  | From date of inclusion to the trial until the date of first documented iRECIST progression or date of death from any cause, whichever came first, assessed up to day 540. | 
| Change of circulating immune cells of treated patients by deep immunophenotyping. | Immunophenotyping of the patients: Detection of about 30 distinct immune sell (sub)types together with their activation markers. The analyses are conducted at time points before (day 0) and before every prescription of ICI (every 14 to 21 days) till progression or end of study at day 540. | The analyses are conducted at time points before (day 0) and before every prescription of ICI (every 14 to 21 days) till progression or end of study at day 540 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Detection of adverse events according to NCI CTAE (v4.0) |  | From date of inclusion to the trial until the date of first documented iRECIST progression or date of death from any cause, whichever came first, assessed up to day 540. | 
| Documentation of corticoid prescription |  | From date of inclusion to the trial until the date of first documented iRECIST progression or date of death from any cause, whichever came first, assessed up to day 540. | 
| Overall survival |  | Till death of the patient or end of study at day 540, whichever came first | 
| Progression free survival |  | From date of inclusion to the trial until the date of first documented iRECIST progression or date of death from any cause, whichever came first, assessed up to day 540. | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Metastatic cancer, Radiotherapy, Immunotherapy, radioimmuno therapy