Title
Phase III Prospective Randomized Trial of Primary Lung Tumor Stereotactic Body Radiation Therapy Followed by Concurrent Mediastinal Chemoradiation for Locally Advanced Non-Small Cell Lung Cancer

Description
This phase III trial compares the effect of adding stereotactic body radiation therapy (SBRT) to standard treatment (image guided radiation therapy [IGRT] and chemotherapy followed by immunotherapy with durvalumab) versus standard treatment alone in treating patients with non-small cell lung cancer that cannot be treated by surgery (inoperable). SBRT uses special equipment to position a patient and deliver radiation to tumors with high precision. This method may kill tumor cells with fewer doses over a shorter period and cause less damage to normal tissue. IGRT is a type of radiation that uses a computer to create picture of the tumor, to help guide the radiation beam during therapy, making it more accurate and causing less damage to healthy tissue. Standard chemotherapy used in this trial consists of combinations of the following drugs: cisplatin, carboplatin, paclitaxel, pemetrexed, and etoposide. Cisplatin is in a class of medications known as platinum-containing compounds. It works by killing, stopping or slowing the growth of tumor cells. Carboplatin is in a class of medications known as platinum-containing compounds. It works in a way similar to the anticancer drug cisplatin, but may be better tolerated than cisplatin. Carboplatin works by killing, stopping or slowing the growth of tumor cells. Paclitaxel is in a class of medications called antimicrotubule agents. It works by stopping the growth and spread of tumor cells. Pemetrexed is in a class of medications called antifolate antineoplastic agents. It works by blocking the action of a certain substance in the body that may help tumor cells multiply. Etoposide is in a class of medications known as podophyllotoxin derivatives. It blocks a certain enzyme needed for cell division and DNA repair and may kill tumor cells. Immunotherapy with durvalumab, may induce changes in body's immune system and may interfere with the ability of tumor cells to grow and spread. Adding SBRT to the standard treatment of IGRT with chemotherapy and immunotherapy may be more effective at treating patients with inoperable non-small cell lung cancer than giving the standard treatment alone.

Objective
PRIMARY OBJECTIVES:

I. To compare the overall survival in patients with stage II-IIIC inoperable node-positive non-small cell lung cancer (NSCLC) after image guided, motion-managed conventional radiotherapy to the primary tumor and nodal metastases (arm 1) or after image guided, motion-managed stereotactic body radiation therapy (SBRT) to the primary tumor followed by conventionally fractionated radiotherapy to nodal metastases (arm 2) both given with concurrent platinum-based chemotherapy.

II. To compare progression-free survival between the experimental arm (arm 2) and control arm (arm 1).

SECONDARY OBJECTIVES:

I. To compare objective response rate (as defined by Response Evaluation Criteria in Solid Tumors [RECIST] version [v] 1.1) between the experimental arm and control arm.

II. To compare the rate of local control between the experimental arm and control arm.

III. To compare patterns of failure (primary, locoregional, or distant) between the experimental arm and control arm.

IV. To compare changes in pulmonary function (forced expiratory volume in 1 second [FEV1] and diffusion capacity of the lung for carbon monoxide [DLCO] assessed at randomization and at 6 and 12 months following completion of radiation therapy) between the experimental arm and control arm.

V. To compare changes in quality of life and patient-reported outcomes assessed from pre-treatment to 3 months following radiation therapy of each treatment arm.

VI. To determine acute and late toxicity profiles of each treatment arm as measured by the Common Terminology Criteria for Adverse Events (CTCAE) v5.

EXPLORATORY OBJECTIVES:

I. To characterize and compare longitudinal quality of life and patient-reported outcomes of each treatment arm.

II. To collect biospecimens at baseline, after SBRT (for arm 2 patients), during last 2 weeks of chemoradiation, and after first dose of consolidation therapy, to allow for future analyses.

III. To collect 4-dimensional (4D) computed tomography (CT) planning scans and radiation dose to calculate regional lung ventilation and explore pre-treatment 4D-CT based ventilation to predict pulmonary toxicity.

IV. To characterize clinical outcomes, toxicities and changes in pulmonary function and quality of life among patients receiving proton and photon radiotherapy.

Treatment Drug: Carboplatin
Drug: Cisplatin
Procedure: Computed Tomography
Biological: Durvalumab
Drug: Etoposide
Radiation: Image Guided Radiation Therapy
Drug: Paclitaxel
Drug: Pemetrexed
Procedure: Positron Emission Tomography
Other: Quality-of-Life Assessment
Other: Questionnaire Administration
Radiation: Stereotactic Body Radiation Therapy

Key Eligibility For full study eligibility, see this study's ClinicalTrials.gov record.

Applicable Disease Sites
Lung

Participating Institutions
UW Health Carbone Cancer Center Rockford; UW Health University Hospital