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

Studien-Informationen Einschlusskriterien Studien-Rationale Studien-Arme Geprüfte Regime

Rekrutierend

NCT-Nummer:
NCT04925583

Studienbeginn:
November 2021

Letztes Update:
05.01.2024

Wirkstoff:
-

Indikation (Clinical Trials):
Lung Neoplasms

Geschlecht:
Alle

Altersgruppe:
Erwachsene (18+)

Phase:
Phase 1

Sponsor:
University Hospital Heidelberg

Collaborator:
-

Studienleiter

Juliane Hörner-Rieber, PD
Principal Investigator
University Hospital Heidelberg

Kontakt

Juliane Hörner-Rieber, PD
Kontakt:
Phone: +49 6221-56
Phone (ext.): 8201
E-Mail: Juliane.Hoerner-Rieber@med.uni-heidelberg.de» Kontaktdaten anzeigen

Adriane Hommertgen, PhD
Kontakt:
Phone: +49 6221 56
Phone (ext.): 8201
E-Mail: adriane.hommertgen@med.uni-heidelberg.de» Kontaktdaten anzeigen

Studienlocations
(1 von 1)

University Hospital of Heidelberg, Radiation Oncology
69120 Heidelberg
(Baden-Württemberg)
GermanyRekrutierend» Google-Maps
Ansprechpartner:
Jürgen Debus, Prof. Dr.
Phone: +49-6221-56
Phone (ext.): 8202
E-Mail: juergen.debus@med.uni-heidelberg.de

Adriane Hommertgen
Phone: +49-6221-56
Phone (ext.): 34091
E-Mail: adriane.hommertgen@med.uni-heidelberg.de» Ansprechpartner anzeigen

Studien-Informationen

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.

Ein-/Ausschlusskriterien

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

Studien-Rationale

Primary outcome:

1. Dose limiting toxicity (DLT) (Time Frame - For 12 months from the beginning of SBRT.):
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.

Secondary outcome:

1. Local tumor control (Time Frame - For 24 months upon enrollment):
Total number of treated ultracentral tumor.

2. Regional tumor control (Time Frame - For 24 months upon enrollment):
Number of tumor leasions in Lungs and Mediastinum excluding the treated ultracentral tumor.

3. Distant tumor Control (Time Frame - For 24 months upon enrollment):
Number of Tumor leasions Outside lungs and mediastinum.

4. Progression-free survival (Time Frame - For 24 months upon enrollment)

5. Overall survival (Time Frame - For 24 months upon enrollment)

6. EORTC QLQ C-30 (Time Frame - For 24 months upon enrollment):
Changes in quality of life following MR-guided ultracentral lung SBRT, according to EORTC QLQ C-30.

7. EORTC QLQ-LC13 (Time Frame - For 24 months upon enrollment):
Changes in quality of life following MR-guided ultracentral lung SBRT, according to EORTC QLQ-LC13.

8. Vital Capacity (Time Frame - For 24 months upon enrollment):
Pulmonary function test parameter.

9. Forced Expiratory Volume in the 1st second (Time Frame - For 24 months upon enrollment):
Pulmonary function test parameter.

10. Cardiovascular function: Longitudinal strain (Time Frame - For 12 months upon enrollment):
Echocardiography.

11. Cardiovascular function: Left ventricular ejection fraction (LVEF) (Time Frame - For 12 months upon enrollment):
Echocardiography.

12. Cardiovascular function: Ratio between early mitral inflow velocity and mitral annular early diastolic velocity (E/e') (Time Frame - For 12 months upon enrollment):
Echocardiography.

13. Cardiovascular function: N-terminal prohormone of brain natriuretic peptide (NT-proBNP) (Time Frame - For 12 months upon enrollment):
Blood Sample.

14. Cardiovascular function: High-sensitive Troponin-T (hsTNT) (Time Frame - For 12 months upon enrollment):
Blood Sample.

15. Dosimetry parameters of MRgRT as compared to CT-based SBRT techniques (Time Frame - through study completion, an average of 1 year)

16. Apparent Diffusion Coefficient (ADC) (Time Frame - 3 months upon SBRT.):
Translational imaging biomarkers based on multiparametric MRI (T1w, T2w and diffusion-weighted) for early detection of pulmonary toxicity and tumor relapse (explorative).

17. Serum cytokines (Time Frame - Immediately and 3 months upon SBRT.):
Translational blood biomarkers (explorative).

18. Immunophenotypes of peripheral blood mononucleated cells (PBMC) (Time Frame - Immediately and 3 months upon SBRT.):
Translational blood biomarkers for early detection of pulmonary toxicity and tumor relapse (explorative).

Studien-Arme

Experimental: Level 0
Total dose 50 Gy, (10 x 5 Gy single dose)
Experimental: Level 1
Total dose 55 Gy, (10 x 5.5 Gy single dose)
Experimental: Level 2
Total dose 60 Gy, (10 x 6 Gy single dose)
Experimental: Level 3
Total dose 65 Gy, (10 x 6.5 Gy single dose)

Geprüfte Regime

Stereotactic body radiotherapy (SBRT):
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

Quelle: ClinicalTrials.gov

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