Combining ICI With SBRT or HypoFrx-RT for ES NSCLC

Study Overview
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Brief Summary
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This study will explore the best dose of radiation to be used when treating stage I-III non-small cell lung cancer (NSCLC) with stereotactic body radiation therapy (SBRT) or hypo-fractionated radiotherapy (HypoFrx-RT) that is delivered in combination with an immune checkpoint inhibitor. Treatments with SBRT or HypoFrx-RT for locally confined NSCLC show positive response which may be further augmented when they are combined with an immune checkpoint inhibitor. Currently, it is not understood what radiation dose is most suitable for such combined treatments and their clinical efficacy in the treatment of early stage (ES) NSCLC. Therefore, this study can help researchers gain insight into what a safe and effective SBRT or HypoFrx-RT dose will be when such radiotherapeutic approaches are combined with concurrent and adjuvant administration of an immune checkpoint inhibitor in the treatment of ES NSCLC.

Detailed Description
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Patients will be assigned to Cohort A or Cohort B based on tumor stage (AJCC 8th Ed.). Cohort A: cT1-T3, N0, M0 (selected cT1, No, M0) Cohort B: cT4, N0, M0; cT1-4, N1-3, M0 Phase I: This portion of the study will utilize a standard 3 + 3 phase I design with three patients enrolled per radiation dose level in each cohort. Enrollment in the two cohorts is independent from one another. In both cohorts, an anti-PD-(L)1 immune checkpoint inhibitor will be given concurrently and adjuvantly with radiotherapy for approximately 1 year. The radiation dose escalation for each cohort is listed below: Cohort A (SBRT): (Optional): 8 Gy x 5 daily fractions Level 1: 9 Gy x 5 daily fractions Level 2: 10 Gy x 5 daily fractions Level 3: 11 Gy x 5 daily fractions Cohort B (HypoFrx-RT): (Optional): 3 Gy x 15 daily fractions Level 1: 3.5 Gy x 15 daily fractions Level 2: 4 Gy x 15 daily fractions DLTs will be based on events occurring during the course of radiotherapy. Concurrent administration of an immune checkpoint inhibitor is defined as: An anti-PD-(L)1 immune checkpoint inhibitor administered with standard dosing (Durvalumab: 1500 mg every 4 weeks) given within 5 days prior to the beginning of radiotherapy. Adjuvant administration of an immune checkpoint inhibitor is defined as: An anti-PD-(L)1 immune checkpoint inhibitor administered with standard dosing (Durvalumab: 1500 mg every 4 weeks) for approximately 1 year or until progression or other discontinuation criteria are met. Phase II: Once a maximum tolerated dose (MTD) is defined in each cohort, this dose will be used as the only radiation dose in each corresponding cohort in the phase II portion of this study. Dosing regimen of the immune checkpoint inhibitor will remain the same as that used in the phase I portion of this study. For this protocol, patients will be followed up to 2 years after the last dose of immune checkpoint inhibitor is administered.

Official Title
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Combining an Immune Checkpoint Inhibitor With SBRT or Hypo-fractionated RT in the Treatment of Stage I-III NSCLC: an Exploratory Study on Radiation Dose and Treatment Efficacy.

Conditions
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Non-small Cell Lung Cancer, Non-small Cell Carcinoma, Non-small Cell Lung Cancer Stage I, Non-small Cell Lung Cancer Stage II, Non-small Cell Lung Cancer Stage III

Intervention / Treatment
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* Radiation: Stereotactic body radiotherapy
* Radiation: Hypofractionated radiotherapy
* Drug: Durvalumab


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Key Inclusion Criteria Informed Consent Stage I-III NSCLC per AJCC 8th. ed. Tumor PD-L1 expression ≥1% preferred Tumor sample submission Tumor staging prior to registration Age ≥ 18 years WHO/ECOG PS of 0, 1, or 2 Life expectancy ≥12 weeks Adequate organ or bone marrow function Evidence of post-menopausal status or negative urinary or serum pregnancy test for female pre-menopausal patients. Exclusion Criteria: Key Exclusion Criteria Mixed small cell and non-small cell lung cancer histology Definitive clinical or radiologic evidence of metastatic disease Patients who received systemic therapy for the current cancer prior to enrollment Thoracic radiotherapy within 5 years with exceptions Major surgery within 28 days prior to enrollment with exception Prior exposure to any anti-PD-1 or anti-PD-L1 antibody History of another primary malignancy with exceptions History of idiopathic pulmonary fibrosis, any pneumonitis, organizing pneumonia (i.e., bronchiolitis obliterans, cryptogenic organizing pneumonia, etc.), or evidence of active pneumonitis on chest PET/CT or CT scan Active or prior documented autoimmune disease with exceptions History of primary immunodeficiency History of allogenic organ or tissue transplantation

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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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Cohort A<br>SBRT to be delivered with concurrent and adjuvant anti-PD-(L)1 immune checkpoint inhibitor. | Radiation: Stereotactic body radiotherapy<br>* An ablative dose of radiation is delivered to the primary tumor target over 1-2 week.<br>* Other names: SBRT;Drug: Durvalumab<br>* an anti-PD-(L)1 immune checkpoint inhibitor is administered concurrently and adjuvantly with radiotherapy.<br>|
| Experimental: Cohort B<br>Hypo-fractionated radiotherapy to be delivered with concurrent and adjuvant anti-PD-(L)1 immune checkpoint inhibitor. | Radiation: Hypofractionated radiotherapy<br>* Hypofractionated radiotherapy is delivered to the primary tumor and any involved lymph node target(s) over 3 weeks.<br>* Other names: HypoFrx-RT;Drug: Durvalumab<br>* an anti-PD-(L)1 immune checkpoint inhibitor is administered concurrently and adjuvantly with radiotherapy.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Maximum tolerated dose (MTD) | MTD in cohort A and cohort B, respectively. | 2 years | 
| The incidence of any adverse events that is >= grade 3 | Adverse events will be graded according to CTCAE v.5.0 | 2 years | 
| Progression-free survival (PFS) | PFS is defined as free from any disease progression or death after combined treatment for NSCLC. | 2 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Local control | To report the local control rate along with the rate of regional control and distant metastasis after combined treatment for NSCLC. | 2 years | 
| Overall survival (OS) | To report OS after combined treatment | 2 years | 
| Quality of Life (QoL) | To determine the QoL pertaining to any cancer patients before and after treatment using the European Organisation of Research and Treatment of Cancer Quality of Life Questionnaire, Core 30 (EORTC QLQ-C30) scales. | 2 years | 
| Quality of Life (QoL), Lung cancer specific | To determine the QoL before and after treatment using the European Organisation of Research and Treatment of Cancer Quality of Life Questionnaire that is specific to lung cancer patients, the Lung Cancer 29(LC 29) scoring scales. | 2 years | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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NSCLC, Stereotactic body radiotherapy, SBRT, Hypofractionated, Radiotherapy