CHEckpoint Inhibition in Combination With an Immunoboost of External Beam Radiotherapy in Solid Tumors

Study Overview
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Brief Summary
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This randomized controlled phase II trial will investigate whether the addition of stereotactic body radiotherapy to checkpoint inhibitor treatment in patients with non-small-cell lung carcinoma, urothelial carcinoma, renal cell carcinoma, melanoma or head-and-neck carcinoma can improve progression-free survival as compared to checkpoint inhibitor monotherapy. The primary outcome is progression-free survival; secondary outcomes include overall survival, response according to iRecist and Recist v1.1 and toxicity.

Official Title
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CHEckpoint Inhibition in Combination With an Immunoboost of External Beam Radiotherapy in Solid Tumors: CHEERS-trial

Conditions
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Urothelial Carcinoma, Melanoma, Renal Cell Carcinoma, Non-small Cell Lung Cancer, Head and Neck Cancer

Intervention / Treatment
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* Drug: Nivolumab or Pembrolizumab or Atezolizumab
* Radiation: SBRT


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Before patient registration, written informed consent must be given according to ICH/GCP and national/local regulations. Histologically confirmed diagnosis of a solid tumour. At least one extracranial tumour lesion available for radiotherapy administration. Patient will receive a checkpoint inhibitor per standard of care in one of the following settings (locally advanced or metastatic): melanoma (1st - 3rd line nivolumab or pembrolizumab); renal cell carcinoma (2nd line nivolumab); non-small cell lung carcinoma (2nd or 3rd line nivolumab, pembrolizumab or atezolizumab); urothelial cell carcinoma ( 1st-3rd line nivolumab, pembrolizumab or atezolizumab); head-& neck squamous cell carcinoma (1st-2nd line pembrolizumab, 2nd line nivolumab). Karnofsky Performance status > 60. Age 18 years or older. Exclusion Criteria: Prior radiotherapy preventing treatment with SBRT. Prior treatment with an anti-PD-(L)1 antibody. Has a known additional malignancy that is progressing or requires active treatment. Exceptions include basal cell carcinoma of the skin or squamous cell carcinoma of the skin that has undergone potentially curative therapy or in situ cervical cancer or prostate cancer that has undergone potentially curative therapy and with normalized PSA. Uncontrolled central nervous system (CNS) metastases at baseline (controlled = previously-treated CNS metastases (surgery ± radiotherapy, radiosurgery, or gamma knife) and who meet both of the following criteria: a) are asymptomatic and b) have no requirement for steroids or enzyme-inducing anticonvulsants), and/or carcinomatous meningitis. Any condition requiring systemic treatment with corticosteroids (> 10 mg daily prednisone equivalent) or other immunosuppressive medication within 14 days prior to the first dose of study drug. Inhaled steroids and adrenal replacement steroid doses > 10 mg daily prednisone equivalent are permitted in the absence of active autoimmune disease. Has a diagnosis of immunodeficiency or history of human immunodeficiency virus (HIV), Hepatitis B or Hepatitis C infection. Mental condition rendering the patient unable to understand the nature, scope and possible consequences of the study. Patient not likely to comply with the protocol; I.e. uncooperative attitude, inability to return for follow-up visits and unlikely to complete the study. Contraindication for radiotherapy. Female subjects of childbearing potential must be willing to use an adequate method of contraception for the course of the study through 120 days after the last dose of study medication.

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
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Experimental arm<br>Stereotactic body radiotherapy concurrent with checkpoint inhibitor treatment: Nivolumab or Pembrolizumab or Atezolizumab + SBRT | Drug: Nivolumab or Pembrolizumab or Atezolizumab<br>* per national standard of care<br>* Other names: Immune checkpoint inhibitor;Radiation: SBRT<br>* Stereotactic body radiotherapy is administered to maximally 3 lesions in 3 fractions of 8Gy prior to the second/third cycle of checkpoint inhibitors.<br>* Other names: Stereotactic body radiotherapy, SABR, Stereotactic ablative radiotherapy;|
| Active Comparator: Control arm<br>Checkpoint inhibitor treatment only: Nivolumab or Pembrolizumab or Atezolizumab monotherapy | Drug: Nivolumab or Pembrolizumab or Atezolizumab<br>* per national standard of care<br>* Other names: Immune checkpoint inhibitor;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression-free survival | Progression-free survival will be defined as the time from randomization to disease progression (as per iRECIST) or death from any cause. | 15 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall survival | Overall survival will be defined as the time from randomization to death from any cause. | 2 years after start trial treatment | 
| Tumor response as per RECIST | Response of non-irradiated lesions will be evaluated as per RECIST v1.1. | 12 weeks | 
| Tumor response as per iRECIST | Response of non-irradiated lesions will be evaluated as per iRECIST | 12 weeks | 
| Incidence of Treatment-Related Adverse Events [safety and tolerability] | Adverse events will be monitored as per Common Terminology Criteria for Adverse Events (CTCAE) v5.0 | 12 weeks | 
| Patient-reported quality of life | Quality of life will be assessed as per EORTC-QLQ C30 questionnaire | 12 weeks | 
| Systemic immune response | Exploratory translational analyses will be performed using blood and fecal samples | 12 weeks | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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radiotherapy, checkpoint inhibitors