Testing the Addition of High Dose, Targeted Radiation to the Usual Treatment for Locally-Advanced Inoperable Non-small Cell Lung Cancer

Study Overview
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Brief Summary
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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.

Detailed Description
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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. OUTLINE: Patients are randomized to 1 of 2 arms. ARM I: Patients undergo conventional IGRT and receive standard of care chemotherapy consisting of paclitaxel intravenously (IV) and carboplatin IV or pemetrexed IV and carboplatin IV or etoposide IV and cisplatin IV or pemetrexed IV and cisplatin IV and then receive durvalumab IV on study. Patients also undergo CT and/or positron emission tomography (PET)/CT during follow up. ARM II: Patients undergo SBRT and conventional IGRT and receive standard of care chemotherapy consisting of paclitaxel IV and carboplatin IV or pemetrexed IV and carboplatin IV or etoposide IV and cisplatin IV or pemetrexed IV and cisplatin IV and then receive durvalumab IV on study. Patients also undergo CT and/or PET/CT during follow up.

Official Title
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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

Conditions
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Locally Advanced Lung Non-Small Cell Carcinoma, Stage IIB Lung Cancer AJCC v8, Stage III Lung Cancer AJCC v8

Intervention / Treatment
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* 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


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Pathologically (histologically or cytologically) proven diagnosis of stage II or III (American Joint Committee on Cancer [AJCC] eighth edition) non-small cell lung cancer (NSCLC) with known PD-L1 status prior to registration Patients must have an identified primary tumor and at least one nodal metastasis (peribronchial/hilar/intrapulmonary, mediastinal/subcarinal, supraclavicular/scalene) Up to 4 cycles of systemic therapy received prior to registration for the current study cancer is allowable; any prior chemotherapy for a different cancer is also permissible The patient must be deemed clinically appropriate for curative intent definitive combined modality therapy, based on the following staging assessments: History/physical examination prior to registration; Magnetic resonance imaging (MRI) scan of the brain (preferred) or CT scan of the brain (if available, contrast is preferred for all neuroimaging) prior to registration; CT chest with IV contrast (if contrast is available and unless contraindicated, such as for abnormal kidney function) prior to registration. PET/CT may be used if the CT portion is of identical diagnostic quality as achieved in a stand-alone CT No evidence of distant metastases based on FDG PET/CT scan obtain within 60 days of registration Primary tumor =< 7 cm Age >= 18 Eastern Cooperative Oncology Group (ECOG) performance status 0-2 Hematologic function (e.g. platelets, leukocytes, hemoglobin) amenable, at the discretion of the treating physician, to allow for treatment with chemotherapy and concurrent radiation therapy Creatinine clearance >= 25 mL/min by the Cockcroft-Gault (C-G) equation Subjects with non-malignant pleural effusion are eligible provided the effusion is not known or demonstrated to be an exudative effusion If a pleural effusion is present, the following criteria must be met to exclude malignant involvement: When pleural fluid is visible on both the CT scan and on a chest x-ray, a pleuracentesis is required to confirm that the pleural fluid is cytologically negative; Effusions that are minimal (i.e., not visible on chest x-ray) that are too small to safely tap are eligible Medical history consistent with the patient being amenable, at the discretion of the treating physician, to allow for treating with consolidation immunotherapy. Patients with known EGFR/ALK mutation at the time of registration are eligible, and these patients can be treated with consolidation durvalumab or chemotherapy at the discretion of the treating physician Patients with a prior or concurrent malignancy whose natural history or treatment does not have the potential to interfere with the safety or efficacy assessment of the investigational regimen Negative pregnancy test =< 14 days prior to registration for participants of childbearing potential The patient or a legally authorized representative must provide study-specific informed consent prior to study entry and, for patients treated in the United States (U.S.), authorization permitting release of personal health information Exclusion Criteria: Prior radiotherapy to the region of the study cancer that would result in overlap of radiation therapy fields that is determined by the treating physician to impede the treatment of the study malignancy Patients without identifiable primary tumor and at least 1 pathologically enlarged lymph node are not eligible (T3-4N0 or T0N1-3 patients are not eligible). At least 1 radiographically-involved lymph node is required, but pathologic confirmation of involvement is not mandated Centrally located primary tumor < 2 cm from involved nodal disease which would result in significant overlap of the primary SBRT and nodal radiation fields. Centrally located is defined as within or touching the zone of the proximal bronchial tree, which is a volume 2 cm in all directions around the proximal bronchial tree (carina, right and left main bronchi, right and left upper lobe bronchi, intermedius bronchus, right middle lobe bronchus, lingular bronchus right and left lower lobe bronchi) Participants who are pregnant or unwilling to discontinue nursing Participants of childbearing potential (participants who may become pregnant or who may impregnate a partner) unwilling to use highly effective contraceptives during therapy and for the Food and Drug Administration (FDA)-labeled contraception timeframe required after the final dose of the selected chemotherapy regimen, because the treatment in this study may be significantly teratogenic

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 |
| --- | --- |
| Active Comparator: Arm I (image guided RT, chemotherapy, immunotherapy)<br>Patients undergo conventional IGRT and receive standard of care chemotherapy consisting of paclitaxel IV and carboplatin IV or pemetrexed IV and carboplatin IV or etoposide IV and cisplatin IV or pemetrexed IV and cisplatin IV and then receive durvalumab IV on study. Patients also undergo CT and/or PET/CT during follow up. | Drug: Carboplatin<br>* Given IV<br>* Other names: Ribocarbo;Drug: Cisplatin<br>* Given IV<br>* Other names: Platosin;Procedure: Computed Tomography<br>* Undergo CT and/or PET/CT<br>* Other names: tomography;Biological: Durvalumab<br>* Given IV<br>* Other names: MEDI4736;Drug: Etoposide<br>* Given IV<br>* Other names: VP16;Radiation: Image Guided Radiation Therapy<br>* Undergo IGRT<br>* Other names: Image-Guided Radiotherapy;Drug: Paclitaxel<br>* Given IV<br>* Other names: Taxol Konzentrat;Drug: Pemetrexed<br>* Given IV<br>* Other names: Pemfexy;Procedure: Positron Emission Tomography<br>* Undergo PET/CT<br>* Other names: proton magnetic resonance spectroscopic imaging;Other: Quality-of-Life Assessment<br>* Ancillary studies<br>* Other names: Quality of Life Assessment;Other: Questionnaire Administration<br>* Ancillary studies<br>|
| Experimental: Arm II (SBRT, image guided RT, chemotherapy, immunotherapy)<br>Patients undergo SBRT and conventional IGRT and receive standard of care chemotherapy consisting of paclitaxel IV and carboplatin IV or pemetrexed IV and carboplatin IV or etoposide IV and cisplatin IV or pemetrexed IV and cisplatin IV and then receive durvalumab IV on study. Patients also undergo CT and/or PET/CT during follow up. | Drug: Carboplatin<br>* Given IV<br>* Other names: Ribocarbo;Drug: Cisplatin<br>* Given IV<br>* Other names: Platosin;Procedure: Computed Tomography<br>* Undergo CT and/or PET/CT<br>* Other names: tomography;Biological: Durvalumab<br>* Given IV<br>* Other names: MEDI4736;Drug: Etoposide<br>* Given IV<br>* Other names: VP16;Radiation: Image Guided Radiation Therapy<br>* Undergo IGRT<br>* Other names: Image-Guided Radiotherapy;Drug: Paclitaxel<br>* Given IV<br>* Other names: Taxol Konzentrat;Drug: Pemetrexed<br>* Given IV<br>* Other names: Pemfexy;Procedure: Positron Emission Tomography<br>* Undergo PET/CT<br>* Other names: proton magnetic resonance spectroscopic imaging;Other: Quality-of-Life Assessment<br>* Ancillary studies<br>* Other names: Quality of Life Assessment;Other: Questionnaire Administration<br>* Ancillary studies<br>Radiation: Stereotactic Body Radiation Therapy<br>* Undergo SBRT<br>* Other names: Stereotactic Ablative Body Radiation Therapy;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall Survival (OS) | Non-inferiority (NI) between arm 2 and arm 1 (reference level) will be evaluated by comparing the upper bound of the 95% confidence interval for the hazard ratio to the pre-specified NI margin. NI of arm 2 will be concluded if the upper bound of the confidence interval is equal to, or falls below, the pre-specified margin at the final analysis. When evaluating the NI of arm 2 in OS, a Cox proportional hazards (PH) model stratified by stratification factors will be used to compute the hazard ratio and associated 95% confidence interval (CI). OS rates will be estimated using the Kaplan-Meier method. If the NI of arm 2 in OS is demonstrated, the superiority of arm 1 in OS will be tested at 1-sided significance level of 0.025 using a stratified log-rank test by adjusting for stratification factors. | Between date of randomization and date of death due to any cause, assessed up to 8 years | 
| Progression-Free Survival (PFS) | The PFS analysis will be conducted using the same methods and stratification factors as the OS analysis. The superiority of arm 2 in PFS will be tested at 1-sided significance level of 0.025 using a stratified log-rank test by adjusting for stratification factors. In the event that the NI of OS is not established, statistical inference of PFS will be considered exploratory in nature only. A Cox PH model stratified by stratification factors will be used to compute the hazard ratio and associated 95% CI. | Between date of randomization and first date of documented progression or death due to any cause, assessed up to 8 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Objective Response Rate (ORR) | ORR (per Response Evaluation Criteria in Solid Tumors [RECIST] 1.1) is defined as the number (%) of patients with at least 1 visit response of complete response (CR) or partial response (PR) and will be based on all randomized patients who have measurable disease. Therefore, data obtained up until progression, or the last evaluable assessment in the absence of progression, will be included in the assessment of ORR. The ORR will be compared between arm 2 versus arm 1 using a Fisher's exact test. A binary response variable for ORR will be used for the analysis with the categories of CR and PR versus stable disease (SD), progressive disease (PD) and inevaluable (NE). | Up to 8 years | 
| Time to progression | Local control will be defined as freedom from local progression, in which a failure is defined as intrathoracic tumor progression (failure in the lobe of the primary tumor or mediastinal lymph nodes) by RECIST 1.1 criteria. Local control will be analyzed as competing risks data based on cause-specific hazards approaches, where deaths without local failure will be considered as a competing event and analyzed as censoring of local failure. The rates at various timepoints (e.g., every 6 months after randomization) and medians of PFS for each arm will be estimated using the Kaplan-Meier method. The associated 95% CI will be calculated using Greenwood's formula and based on a log-log transformation applied on the survival function. Results from an unstratified analysis will also be provided. | Up to 8 years | 
| Time to primary, locoregional, or distant failure | Competing risks analysis will be used to analyze times to primary failure, locoregional failure and distant failure as the first failure. Competing events include primary failure, locoregional failure, distant failure and deaths without any failures. Rates at various timepoints (i.e., every 6 months after randomization) for each arm will be estimated using the cumulative incidence function. The associated 95% CI will be calculated using the Delta method and based on a log-log transformation applied on the estimated cumulative incidence functions. Statistical inferences of the development of each failure between arms will be based on cause-specific hazards using the log-rank test and Cox proportional hazard model. In addition, Gray's test and the Fine-Gray model will also be used to provide statistical inferences between arms based on cumulative incidence functions and subdistribution hazards. | Up to 8 years | 
| Changes in pulmonary function | Includes forced expiratory volume in 1 second (FEV1) and diffusion capacity of the lung for carbon monoxide (DLCO). Changes in pulmonary function (FEV1 and DLCO) will be summarized with descriptive statistics, and compared with Wilcoxon rank-sum test. The descriptive statistics of changes in FEV1 and diffusion capacity before and after treatment will be reported by treatment arm and by response categories (complete response; partial response; stable disease; progressive disease). Linear regression will be used to model changes with adjustment for treatment arms and possibly other baseline covariates, if applicable. The grade 3-5 NRG Oncology Pulmonary Toxicity Scale for changes will be reported with the frequency and grade by arm. Logistic regression will be used to model the distribution of the NRG Oncology Pulmonary Toxicity Scale by arms with and without adjustment for covariates. | From randomization to 6 months or 12 months | 
| Patient Reported Outcomes | Functional Assessment of Cancer Therapy Lung Questionnaire trial outcome index deterioration rates at 3 months and associated 95% confidence interval will be calculated for each treatment group, based on all randomized subjects. Clopper-Pearson method will be used for calculating 95% CI. The deterioration rates of each arm will also be compared using Cochran-Mantel-Haenszel Test, stratified by PD-L1 expression and T-stage. | At 3, 12, and 24 months | 
| Incidence of adverse events | For each patient, the maximum severity reported will be used in the summaries. Adverse events will be summarized regardless of relationship to protocol treatment as assessed by the investigator. Treatment-related adverse events using National Cancer Institute's Common Terminology Criteria for Adverse Events (CTCAE) will be presented in statistical analysis reports/publications in CTCAE version 5. Adverse event rates will be reported with the frequency and severity (e.g., type, grade, and attribution) by arm. | Up to 8 years |