Clinical trial NCT04925583: Magnetic Resonance Guided Adaptive Stereotactic Body Radiotherapy for Lung Tumors in Ultracentral Location
Official title: Magnetic Resonance Guided Adaptive Stereotactic Body Radiotherapy for Lung Tumors in Ultracentral Location
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE1
Conditions: Lung Cancer
Keywords: SBRT
IGRT
MR-guidance
ultracentral lung tumor
NSCLC
oligometastases
Lead sponsor: University Hospital Heidelberg
Sponsor class: OTHER
First posted: 2021-06-14
Enrollment: 38
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SEQUENTIAL
Intervention 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
Primary purpose: TREATMENT

Brief summary: 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: 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.

Eligibility criteria: 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

Primary outcomes:
measure: Dose limiting toxicity (DLT)
timeFrame: For 12 months from the beginning of SBRT.
Secondary outcomes:
measure: Local tumor control
timeFrame: For 24 months upon enrollment
measure: Regional tumor control
timeFrame: For 24 months upon enrollment
measure: Distant tumor Control
timeFrame: For 24 months upon enrollment
measure: Progression-free survival
timeFrame: For 24 months upon enrollment
measure: Overall survival
timeFrame: For 24 months upon enrollment
measure: EORTC QLQ C-30
timeFrame: For 24 months upon enrollment
measure: EORTC QLQ-LC13
timeFrame: For 24 months upon enrollment
measure: Vital Capacity
timeFrame: For 24 months upon enrollment
measure: Forced Expiratory Volume in the 1st second
timeFrame: For 24 months upon enrollment
measure: Cardiovascular function: Longitudinal strain
timeFrame: For 12 months upon enrollment
measure: Cardiovascular function: Left ventricular ejection fraction (LVEF)
timeFrame: For 12 months upon enrollment
measure: Cardiovascular function: Ratio between early mitral inflow velocity and mitral annular early diastolic velocity (E/e')
timeFrame: For 12 months upon enrollment
measure: Cardiovascular function: N-terminal prohormone of brain natriuretic peptide (NT-proBNP)
timeFrame: For 12 months upon enrollment
measure: Cardiovascular function: High-sensitive Troponin-T (hsTNT)
timeFrame: For 12 months upon enrollment
measure: Dosimetry parameters of MRgRT as compared to CT-based SBRT techniques
timeFrame: through study completion, an average of 1 year
measure: Apparent Diffusion Coefficient (ADC)
timeFrame: 3 months upon SBRT.
measure: Serum cytokines
timeFrame: Immediately and 3 months upon SBRT.
measure: Immunophenotypes of peripheral blood mononucleated cells (PBMC)
timeFrame: Immediately and 3 months upon SBRT.
Other outcomes:
Locations:
city: Heidelberg
country: Germany
facility: University Hospital of Heidelberg, Radiation Oncology
Study officials:
affiliation: University Hospital Heidelberg
name: Juliane Hörner-Rieber, PD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Regnery S, Ristau J, Weykamp F, Hoegen P, Sprengel SD, Paul KM, Buchele C, Kluter S, Rippke C, Renkamp CK, Pohl M, Meis J, Welzel T, Adeberg S, Koerber SA, Debus J, Horner-Rieber J. Magnetic resonance guided adaptive stereotactic body radiotherapy for lung tumors in ultracentral location: the MAGELLAN trial (ARO 2021-3). Radiat Oncol. 2022 May 25;17(1):102. doi: 10.1186/s13014-022-02070-x.