Radical-Dose Image Guided Radiation Therapy in Treating Patients With Metastatic Non-small Cell Lung Cancer Undergoing Immunotherapy

Study Overview
=================
Brief Summary
-----------------
This phase II trial studies how well radical-dose image guided radiation therapy works in treating patients with non-small cell lung cancer that has spread to other places in the body who are undergoing immunotherapy. Radiation therapy uses high energy x-rays to kill tumor cells and shrink tumors. Giving radical-dose image guided radiation therapy to patients with non-small cell lung cancer may help to improve response to immunotherapy anti-cancer treatment.

Detailed Description
-----------------
PRIMARY OBJECTIVES: I. Determine if progression-free survival at 24 weeks with this treatment combination is improved compared to historical controls who received immunotherapy without radiation therapy. SECONDARY OBJECTIVES: I. Assess acute (0-6 months) and late (> 6 months) grade 3-5 toxicity. II. Assess overall survival. III. Correlate circulating tumor deoxyribonucleic acid (DNA) (ratio of post-radiation therapy [RT] to pre-RT level) with radiographic response. IV. Correlate immune markers in peripheral blood with radiographic response. TERTIARY OBJECTIVES: I. Analyze progression-free survival with immune-related response criteria. II. Measure time to discontinuation of study immunotherapy agent. III. Assess patterns of progression. OUTLINE: Patients are assigned to 1 of 2 arms. ARM I: Patients undergo radical-dose image guided radiation therapy daily for up to 10 days (within 2 weeks) while undergoing standard of care immunotherapy. Arm II: Patients who decline to undergo radiation therapy receive standard of care immunotherapy. After completion of study treatment, patients are followed up at 30 days and every 6 months thereafter.

Official Title
-----------------
Radical RADiotherapy and Immunotherapy for Metastatic CAncer of the Lung (RRADICAL)

Conditions
-----------------
Stage IV Non-Small Cell Lung Cancer

Intervention / Treatment
-----------------
* Radiation: Image-guided Radiation Therapy
* Drug: Immunotherapy (physician's choice for standard of care immunotherapy)


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Has stage IV non-small cell lung cancer, or initially stage I-III disease with distant metastatic recurrence Age ≥ 18 Has been receiving anti-PD-1 or anti-PD-L1 immunotherapy for at least four weeks (refer to section 4.2.1) Has had restaging imaging after initiation of immunotherapy, at least 4 weeks after pre-immunotherapy baseline imaging. CT or PET/CT of at least chest/upper abdomen must be performed within 4 weeks prior to registration. For patients with history of brain metastases, brain MRI or CT is required within 4 weeks of registration; for other patients brain MRI or CT is required within 12 weeks of registration. Diagnostic PET/CT performed as part of radiation simulation can be used as the restaging imaging. Most recent imaging shows measurable disease as defined by RECIST 1.1 Evaluation by a Stanford medical oncologist must show: The patient is expected to continue on immunotherapy for at least three more months Imaging must show response, stable disease, or modest progression If there is modest progression, the patient must be clinically stable in terms of performance status and overall disease-related symptoms Has at least one extracranial tumor safely treatable with radical-dose radiation therapy and that has not been previously treated with radiation ECOG performance status 0-2 Has the ability to understand and the willingness to sign a written informed consent document. Exclusion Criteria: Untreated brain metastases, if not planned to be treated in this course of radiation therapy Pregnancy or women of childbearing potential not willing/able to use contraception during protocol treatment

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

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

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

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

Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Immunotherapy plus Image-guided Radiation Therapy<br>Patients undergo radical-dose image guided radiation therapy daily for up to 10 days (within 2 weeks) while continuing their prior treatment with the treating physician's choice of regular medical care immunotherapy. | Radiation: Image-guided Radiation Therapy<br>* Ablative treatment as 50 Gy in 5 or 10 fractions. Non-ablative treatment as 27 Gy in 3 fractions, or 40 Gy in 10 fractions.<br>* Other names: IGRT;Drug: Immunotherapy (physician's choice for standard of care immunotherapy)<br>* Continue regular medical care immunotherapy. Other than being an anti-PD-1 or anti-PD-L1 immunotherapy, the agent, dose, and schedule is not specified by protocol.<br>* Other names: biologic therapy;|
| Active Comparator: Immunotherapy Alone (Regular Medical Care)<br>Patients who decline to undergo radiation therapy will continue their prior treatment with the treating physician's choice of regular medical care immunotherapy. | Drug: Immunotherapy (physician's choice for standard of care immunotherapy)<br>* Continue regular medical care immunotherapy. Other than being an anti-PD-1 or anti-PD-L1 immunotherapy, the agent, dose, and schedule is not specified by protocol.<br>* Other names: biologic therapy;|

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

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression-free survival | Defined as proportion of patients without Response Evaluation Criteria in Solid Tumors version 1.1 disease progression or death 24 weeks from date of study entry. | At 24 weeks after study entry | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in circulating tumor deoxyribonucleic acid levels as measured using CAncer Personalized Profiling by deep Sequencing | Will correlate with radiographic response. Plasma biomarkers (e.g. cell free deoxyribonucleic acid level) will be summarized using medians and interquartile ranges; changes in biomarkers will be assessed using the Wilcoxon signed rank test. Correlation of biomarkers with radiographic response will be evaluated using a Wilcoxon rank sum test on patients with and without the event of interest. If feasible, these analyses will be supplemented by more formal analyses with the Cox model. | Baseline up to 1 year after study entry | 
| Change in immune marker levels as measured from peripheral blood using flow cytometry performed by the Human Immune Monitoring Core at Stanford University | Will correlate with radiographic response. | Baseline up to 1 year after study entry | 
| Incidence of acute (0-6 months) and late (> 6 months) grade 3-5 toxicity | Measured with Common Terminology Criteria for Adverse Events version 4. | Up to 4 years after study entry | 
| Overall survival | The electronic medical record will be monitored for patient deaths. | Time from study entry to death, assessed up to 4 years after study entry |