A Trial of Integrating SBRT With Targeted Therapy in Stage IV Oncogene-driven NSCLC

Study Overview
=================
Brief Summary
-----------------
This research study is studying a type of radiation therapy called Stereotactic Body Radiation Therapy (SBRT) as a possible treatment for stage IV non-small cell lung cancer (NSCLC) that has a mutated epidermal growth factor receptor (EGFR) or or displaced anaplastic lymphoma receptor tyrosine kinase (ALK) or ROS proto-oncogene 1 (ROS1) gene (= oncogene-driven NSCLC) and for which the subject has been receiving treatment with a targeted biological agent such as erlotinib, crizotinib, or other drugs.

Detailed Description
-----------------
This research study is a Phase II clinical trial. Phase II clinical trials test the safety and effectiveness of an investigational intervention to learn whether the intervention works in treating a specific disease. The investigational intervention in this study is SBRT with proton or photon radiation (explained below). Investigational means that the intervention is being studied. SBRT and proton radiation therapy are FDA approved radiation delivery systems. However, using it as a treatment for stage IV NSCLC is still investigational. SBRT is a specialized, technologically advanced type of external beam radiation therapy that pinpoints high doses of radiation directly on the cancer. Because of high precision, these treatments spare healthy tissue and are associated with fewer side effects. SBRT is very different from conventional therapy where radiation is delivered in small doses given daily over the course of several weeks. For SBRT, the total dose of radiation is typically administered in 4-5 daily sessions. SBRT can be delivered with standard, so called photon radiation, or proton beam. Neither of these two types of radiation is generally superior over the other. There are technical differences between these two, and depending on tumor location, size, shape, and other factors, the investigators will decide which type of radiation to use for which treatment. After the screening procedures confirm you are eligible to participate in the research study: - Each participant will receive stereotactic treatment course (SBRT with protons or photons) to the area of their tumor.

Official Title
-----------------
A Phase II Trial of Integrating Stereotactic Body Radiation Therapy With Selective Targeted Therapy in Stage IV Oncogene-driven Non-Small Cell Lung Cancer

Conditions
-----------------
Non-small Cell Lung Cancer Metastatic, Targetable Oncogenes (EGFR, ALK, ROS1)

Intervention / Treatment
-----------------
* Radiation: SBRT with protons or photons


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Histologically or cytologically confirmed non-small cell lung cancer (NSCLC) with any actionable mutation or translocation in EGFR, ALK, or ROS1 Stage IV disease (AJCC Staging system 7th edition) Within 6 months of initiating their first TKI treatment regimen Stable or responding systemic disease to TKI (no evidence of progression) on the most recent staging studies. The complete extent of the current residual systemic disease must be deemed amenable to SBRT as per review of imaging studies by a radiation oncologist, based on the following criteria: Lung: 1-3 lesions (including the primary) of maximum size 5 cm in longest diameter. A minimum size 1 cm in the longest diameter is recommended. (Patients with a malignant pleural effusion prior to the start of TKI therapy will be considered eligible for SBRT if there is complete radiographic resolution of the effusion while on systemic therapy); Spine: Bone lesions must be limited to the spine. A maximum of 2 spinal metastases will be considered for SBRT, with each site spanning 1-3 vertebral bodies. A minimum size of 1 cm in longest diameter is recommended. SBRT may target sclerotic lesions that persist following TKI therapy; GI: 1-4 liver metastases of maximum size 5 cm in longest diameter and/or 1-2 adrenal metastases of maximum 4 cm size in longest diameter. A minimum size of 1 cm in longest diameter is recommended. In addition: CNS: 1-4 brain metastases of maximum size 3cm in longest diameter. However, these should be treated with standard-of-care SRS and will not be defined as target lesions for purposes of this protocol. A maximum number of 5 target lesions outside the brain, excluding the lung primary, is recommended to ensure that enrollment is limited to patients with low-burden disease and that treatments can be delivered within the specified time frame. History of prior radiation therapy to brain or skeleton is allowed, but should have occurred > 2 months from enrollment. Age at least 18 years. Life expectancy of greater than 6 months. ECOG performance status ≤ 2. Women of child-bearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry and for the duration of study participation. Should a woman become pregnant or suspect she is pregnant while participating in this study, she should inform her treating physician immediately. A negative serum or urine pregnancy test within 2 weeks of registration for women of childbearing potential is required. Ability to understand and the willingness to sign a written informed consent document. Exclusion Criteria: Residual hilar or mediastinal lymph node disease (size > 1cm in short-axis diameter on CT). Non-malignant etiologies for enlarged lymph nodes may be evaluated per standard clinical practice. Participants who have received prior radiation therapy to anatomical sites other than brain or skeleton. Uncontrolled intercurrent illness including, but not limited to ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements. Patients who are pacemaker or defibrillator-dependent as these devices may not be operated concurrently with delivery of proton beam radiation. Pregnant or lactating women, as treatment involves unforeseeable risks to the embryo or fetus.

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
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: SBRT with protons or photons<br>Dosage determined by treating physician If there is more than one active site of cancer, additional site(s) will be treated with stereotactic treatment courses. The total duration of SBRT courses (from the first day of any SBRT course to the last day of any SBRT course) will not exceed 4 months. | Radiation: SBRT with protons or photons<br> <br> * Other names: Stereotactic body radiation therapy;|

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

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Frequency of distant failures (DF) after SBRT | To analyze frequency of patients with DF (with or without concurrent original site failure) in oncogene-driven NSCLC patients with residual oligometastatic disease at 12 months after initiation of SBRT | 12 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants with Adverse Events | To describe toxicities of treatment using CTCAE v4.0 | Up to 2 years | 
| Progression Free Survival | To analyze median progression free survival time | Duration of time from documented start of TKI therapy to time of progressive disease, assessed up to 5 years. | 
| Overall Survival | To analyze median survival time and 2-year overall survival rate | Duration of time from the start of documented TKI therapy for up to 5 years or until time of death, whichever occurs first. | 
| Pattern of original and distant site failures (OF and DF) |  | 2 Years | 
| Local control of lesions treated with SBRT |  | The duration of LC is defined as the time period between the completion of SBRT to the time of objective progressive disease, assessed up to 5 years. | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Non-small cell lung cancer, Metastatic, EGFR, ALK, ROS1, Stereotactic Body Radiation Therapy