Magnetic Resonance Guided Adaptive Stereotactic Body Radiotherapy for Lung Tumors in Ultracentral Location

Study Overview
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Brief Summary
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MAGELLAN is a phase-I dose escalation trial that aims to identify the maximum tolerated dose (MTD) of MR-guided SBRT of ultracentral lung Tumors (primary objective). Thus, a maximum of 38 patients with ultracentral lung tumors (overlap of the planning target volume with the proximal bronchial tree and/or esophagus) will receive MR-guided SBRT including gated dose delivery and daily plan adaptation on a 0.35 MR-linac System. Dose levels are as follows: 0 (de-escalation): 10 x 5.0Gy 1 (start): 10 x 5.5Gy 2: 10 x 6.0Gy 3: 10 x 6.5Gy Dose escalation is performed according to a time-to-event continual reassessment method (TITE-CRM) with backup element. Patients are observed individually for 12 months to detect potential dose limiting toxicity (DLT = primary endpoint) and for a total of 24 months to detect potential tumor relapse.

Detailed Description
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Stereotactic body radiotherapy (SBRT) is a well-established local treatment method for early-stage NSCLC or lung metastases. However, clinicians are restricted in the utilization of sufficiently high radiation doses when the lung tumor is in ultracentral location next to radiosensitive organs-at-risk (OAR, e.g. the central airways or the esophagus). MR-guided SBRT can minimize the dose to these OAR by advanced techniques to correct for interfractional (daily plan adaptation) and intrafractional motion (respiratory gating, i.e. synchronization of beam delivery to the patient's breathing). Consequently, the MAGELLAN trial uses MR-guided SBRT to enable safe dose escalation to ultracentral lung tumors. The primary objective of this phase I dose escalation trial is to detect the maximum tolerated dose of MR-guided SBRT to ultracentral lung tumors with a dose limiting toxicity (DLT) rate = 35%. This dose should yield the optimum balance between acceptable treatment toxicity and good tumor control. The corresponding primary endpoint is the observation of the binary outcome dose-limiting toxicity (DLT) within 12 months from start of radiation. Secondary objectives include description of tumor control, patient survival and patient-reported outcomes, assessment of longitudinal cardiopulmonary function and dosimetry evaluations. Exploratory objectives include detection of early biomarkers of pulmonary toxicity and tumor response from multiparamtetric thoracic MRI examinations as well as peripheral blood samples before and early after treatment. A maximum of 38 adult patients may be accrued. Inclusion criteria encompass indication for pulmonary SBRT, ultracentral lung tumor location defined as overlap of the planning target volume (PTV) with the proximal bronchial tree or esophagus and a maximum tumor diameter ≤ 5cm. MR-guided SBRT is delivered on a 0.35T MR-Linac (6MV linear accelerator) with daily plan adaptation and gated dose delivery. Four dose levels may be employed: 0 (de-escalation): 10 x 5.0Gy 1 (start): 10 x 5.5Gy 2: 10 x 6.0Gy 3: 10 x 6.5Gy Dose level 0 represents a de-escalation step which is deemed safe by retrospective clinical data. Dose level 3 confidently reaches a BED10 > 100 Gy necessary for adequate local tumor control in the lung according to hitherto data. Individual observation time for DLTs is 12 months. Dose escalation is performed in dose escalation cohorts consisting of three patients (N = 3) and the first cohort starts at dose level 1 (10 x 5.5 Gy). A time-to-event continual reassessment method (TITE-CRM) is used to recommend the dose level for the next cohort after a cumulative observation time of 18 months. TITE-CRM accounts for all available data at any given time to estimate DLT rates for each dose level and will recommend the dose level closest to the MTD. Admissible patients who present during the cumulative observation time are included as backup patients and treated on the dose level below the current recommendation. An escalation with overdose control (EWOC) approach is applied to prevent treatment with too toxic doses. According to the stopping criteria, patient accrual will be stopped after including 36 patients or 40 months after the first subject in date (recruitment of current dose escalation cohort may be completed), in case that estimation of the MTD is sufficiently certain or if all dose levels appear too toxic. After patient accrual has been stopped and all patients have completed their individual observation time, a final dose recommendaton will be performed which represents the MTD estimate. During follow-up, patients receive clinical assessments (3 monthly), thoracic CT- (3-monthly) and MR-imaging (after 3 months), one cardiology assessment (after 12 months), pulmonary function testing (12-monthly) and peripheral blood samples (last treatment day, after 3 months) for a total of 2 years after treatment.

Official Title
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Magnetic Resonance Guided Adaptive Stereotactic Body Radiotherapy for Lung Tumors in Ultracentral Location

Conditions
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Lung Cancer

Intervention / Treatment
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* Radiation: Stereotactic body radiotherapy (SBRT)


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: ultracentral location of the lung tumor, which is defined as an expected contact or overlap of the planning target volume with the proximal bronchial tree or esophagus at the time of consultation indication for SBRT of the ultracentral pulmonary tumor maximum diameter of the ultracentral pulmonary tumor < 5cm age > 18 years of age Karnofsky Performance Score > 70% (ECOG Score 0 - 2) ability to lie still on the MR-linac table for at least one hour ability to hold one's breath for more than 20 seconds successful completion of MRgRT simulation for women with childbearing potential, adequate contraception. ability of subject to understand character and individual consequences of the clinical trial written informed consent (must be available before enrolment in the trial) Exclusion Criteria: refusal of the patients to take part in the study previous radiotherapy of the lung and mediastinum, if previous and current target volumes overlap patients who have not yet recovered from acute toxicities of prior therapies (planned) treatment with vascular endothelial growth factor (VEGF) inhibitors, e.g. Bevacizumab, within the time interval 2 weeks before and 2 weeks after SBRT pregnant or lactating women contraindications against performing MRI scans (pacemakers, other implants making MRI impossible) participation in another competing clinical study or observation period of competing trials

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
Intervention Model: Sequential Assignment
Interventional Model Description: Dose escalation, Arm 1: Level 0, 5.0 Gy, 10 fractions Arm 2: Level 1, 5.5 Gy, 10 fractions Arm 3: Level 2, 6.0 Gy, 10 fractions Arm 4: Level 3, 6.5 Gy, 10 fractoins
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Level 0<br>Total dose 50 Gy, (10 x 5 Gy single dose) | Radiation: Stereotactic body radiotherapy (SBRT)<br>* level 0 (de-escalation): 10 x 5.0Gy level 1 (start): 10 x 5.5Gy level 2: 10 x 6.0Gy level 3: 10 x 6.5Gy<br>|
| Experimental: Level 1<br>Total dose 55 Gy, (10 x 5.5 Gy single dose) | Radiation: Stereotactic body radiotherapy (SBRT)<br>* level 0 (de-escalation): 10 x 5.0Gy level 1 (start): 10 x 5.5Gy level 2: 10 x 6.0Gy level 3: 10 x 6.5Gy<br>|
| Experimental: Level 2<br>Total dose 60 Gy, (10 x 6 Gy single dose) | Radiation: Stereotactic body radiotherapy (SBRT)<br>* level 0 (de-escalation): 10 x 5.0Gy level 1 (start): 10 x 5.5Gy level 2: 10 x 6.0Gy level 3: 10 x 6.5Gy<br>|
| Experimental: Level 3<br>Total dose 65 Gy, (10 x 6.5 Gy single dose) | Radiation: Stereotactic body radiotherapy (SBRT)<br>* level 0 (de-escalation): 10 x 5.0Gy level 1 (start): 10 x 5.5Gy level 2: 10 x 6.0Gy level 3: 10 x 6.5Gy<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Dose limiting toxicity (DLT) | Observation of the binary outcome dose-limiting toxicity (DLT). DLTs are defined in a catalogue of mainly pulmonary, esophageal and cardiac toxicity based on the CTCAE in Version 5.0. | For 12 months from the beginning of SBRT. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Local tumor control | Total number of treated ultracentral tumor. | For 24 months upon enrollment | 
| Regional tumor control | Number of tumor leasions in Lungs and Mediastinum excluding the treated ultracentral tumor. | For 24 months upon enrollment | 
| Distant tumor Control | Number of Tumor leasions Outside lungs and mediastinum. | For 24 months upon enrollment | 
| Progression-free survival |  | For 24 months upon enrollment | 
| Overall survival |  | For 24 months upon enrollment | 
| EORTC QLQ C-30 | Changes in quality of life following MR-guided ultracentral lung SBRT, according to EORTC QLQ C-30. | For 24 months upon enrollment | 
| EORTC QLQ-LC13 | Changes in quality of life following MR-guided ultracentral lung SBRT, according to EORTC QLQ-LC13. | For 24 months upon enrollment | 
| Vital Capacity | Pulmonary function test parameter. | For 24 months upon enrollment | 
| Forced Expiratory Volume in the 1st second | Pulmonary function test parameter. | For 24 months upon enrollment | 
| Cardiovascular function: Longitudinal strain | Echocardiography. | For 12 months upon enrollment | 
| Cardiovascular function: Left ventricular ejection fraction (LVEF) | Echocardiography. | For 12 months upon enrollment | 
| Cardiovascular function: Ratio between early mitral inflow velocity and mitral annular early diastolic velocity (E/e') | Echocardiography. | For 12 months upon enrollment | 
| Cardiovascular function: N-terminal prohormone of brain natriuretic peptide (NT-proBNP) | Blood Sample. | For 12 months upon enrollment | 
| Cardiovascular function: High-sensitive Troponin-T (hsTNT) | Blood Sample. | For 12 months upon enrollment | 
| Dosimetry parameters of MRgRT as compared to CT-based SBRT techniques |  | through study completion, an average of 1 year | 
| Apparent Diffusion Coefficient (ADC) | Translational imaging biomarkers based on multiparametric MRI (T1w, T2w and diffusion-weighted) for early detection of pulmonary toxicity and tumor relapse (explorative). | 3 months upon SBRT. | 
| Serum cytokines | Translational blood biomarkers (explorative). | Immediately and 3 months upon SBRT. | 
| Immunophenotypes of peripheral blood mononucleated cells (PBMC) | Translational blood biomarkers for early detection of pulmonary toxicity and tumor relapse (explorative). | Immediately and 3 months upon SBRT. | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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SBRT, IGRT, MR-guidance, ultracentral lung tumor, NSCLC, oligometastases