IMMUNOtherapy and Stereotactic ABlative Radiotherapy (IMMUNOSABR) a Phase II Study

NCT03705403 | Terminated Phase 2 DMC

• 1 other identifier: UM2018IMMUNOSABR2RLPL
• Study Type: interventional
• Target: 88
• Locations: 6 countries
• Sites: 15

Brief Summary

This will be a phase II trial testing if the combination of stereotactic ablative body radiotherapy (SABR) and L19-IL2 improve the progression-free survival in patients with limited metastatic non-small cell lung cancer (NSCLC). The trial consists of one cohort with two arms; C-arm and an E-arm. Patients with oligometastatic disease will receive SABR to minimal 1 and max all metastatic sites (max 5 sites irradiated) and patients with diffuse metastatic lesions (6 to max 10) will receive radiotherapy to max 5 sites. In the experimental arm, immunotherapy will be given after irradiation.

Conditions

NSCLC Stage IV; Metastatic Disease

Outcome Measures

Primary Outcomes (1)

• Progression-free survival

  The main objective of the trial is to test the hypothesis that the combination of (SAB)R and L19-IL2 in patients with metastatic NSCLC will resulting in improved progression-free survival (PFS) compared to the SOC.

  18 months after randomization of the last patient

Secondary Outcomes (7)

• Overall survival

  18 months after randomization of the last patient

• Change in score of The EORTC quality of life questionnaire (QLQ) core module (C30)

  baseline and at 3, 6, 9, 12, 15, 18, 21, 24 months after treatment

• Change in score of The EORTC quality of life questionnaire (QLQ) - Lung cancer module (LC13)

  baseline and at 3, 6, 9, 12, 15, 18, 21, 24 months after treatment

• Change in score of The Euro Quality of Life - 5 dimensions - 5 levels (EQ-5D-5L)

  baseline and at 3, 6, 9, 12, 15, 18, 21, 24 months after treatment

• Change in score of The Euro Quality of Life (EQ) visual analogue scale (VAS)

  baseline and at 3, 6, 9, 12, 15, 18, 21, 24 months after treatment

Study Arms (2)

Control

ACTIVE COMPARATOR

Standard of Care (SOC) according to the local and national guidelines: (wait and see or surgery and/or chemotherapy and/or standard (symptomatic) radiation therapy and/or SABR (oligometastatic disease)

Radiation: Radiation

Experimental treatment

EXPERIMENTAL

Standard of Care (SOC SABR (oligometastatic disease) or radiation therapy (diffuse disease) + L19-IL2 up to 6 cycles (Darleukin)

Drug: Darleukin; Radiation: Radiation

Interventions

Darleukin DRUG

The product name refers to the molecule structure, in fact, L19-IL2 is a recombinant fusion protein composed of two moieties: L19, a human monoclonal antibody fragment in the single chain Fv (scFv) format, bound via a flexible linker to IL2, the human cytokine Interleukin-2.

Also known as: L19 - IL2

Experimental treatment

Radiation RADIATION

Radiotherapy

Also known as: Radiotherapy

Control; Experimental treatment

Eligibility Criteria

• Age: 18 Years+
• Gender Eligibility Details: trying to include 50% M/F in each group
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Oligometastatic disease (≤5 metastases)
• Histological confirmed limited metastatic adult NSCLC patients, regardless of the PD-L1 status.
• Maximum of 5 metastatic lesions, maximum two brain lesion with a total cumulative diameter of 5cm is allowed.
• SOC baseline imaging e.g MRI and/or PET-CT and CT-brain or MRI brain and/or CT-scan with at least covering thorax-upper abdomen-brain, within 6 weeks prior to randomisation.
• If a patient has unclear lesions in the liver or brain an MRI would be advised following the ESMO guidelines.
• o In patients with 2 lung tumours, it can be unclear if the patient has 2 concurrent primary tumours or a primary lung tumour with 1 metastasis. In this case, the local multidisciplinary tumour board will decide whether the patient has an M1 disease or not.
• Previous treatment: Prior cancer treatments are allowed but must be discontinued for at least 4 weeks before randomisation. In case of maintenance chemotherapy, this therapy will only be started after the end of the L19-IL2 treatment or only in case of Anti-PD(L)1 treatment, during L19-IL2 therapy.
• Age of 18 years or older.
• WHO performance status 0-1;
• Adequate bone marrow function, evaluated in the local laboratory (Lab): Absolute Neutrophil Count (ANC) of ≥ 1.0 x 109 /L, platelet count ≥ 100 x 109/L, Haemoglobin (Hb) ≥ 6.0 mmol/L (or 9.67 g/dL) (it is allowed to give a blood transfusion if Hb is initially too low);
• Adequate hepatic function (evaluated in the local lab): total bilirubin ≤ 1.5 x upper limit of normal (ULN) for the institution; ALT, AST, and alkaline phosphatase ≤ 2.5 x ULN for the institution or ≤ 5 in case of liver metastasis);
• Adequate renal function (evaluated in the local lab): creatinine clearance of at least 40 ml/min;
• Adequate endocrine (TSH, FT4) function, local guidelines
• The patient is capable of complying with study procedures;
• Life expectancy of at least 12 weeks;

You may not qualify if:

• More than 10 metastatic lesions.
• More than 2 brain metastatic lesions.
• brain metastases with a cumulative diameter larger than 5 cm.
• Patients with non-infectious pneumonitis, uncontrolled thyroid disease, pleuritis, pericarditis and peritonitis carcinomatosis.
• Patients who received live vaccines 30 days or fewer prior to enrolment.
• Patients who are already actively participating in another study.
• Patients who need simultaneous radiation on the primary tumour and metastatic lesion(s). For these patients it might be an option to treat the primary tumour first although this is not mandatory for this study. There must be minimal four weeks between last treatment and randomisation.
• Whole brain radiotherapy (WBRT) is not allowed, although it is accepted when given at least 4 weeks prior to randomisation or after the treatment period. Patients with stable brain metastases are not excluded.
• Previous radiotherapy to an area that would be re-treated by (SAB)R, resulting in overlap of the high dose areas.
• Maintenance therapy with Anti-PD(L)1 treatment combined with chemotherapy is not allowed during treatment ((SAB)R and L19-IL2 cycles).
• Other active malignancy or malignancy within the last 2 years (except localised skin basal/squamous cell carcinoma, non-muscle invasive carcinoma of the bladder or in situ carcinoma from any site).
• Concomitantly administered glucocorticoids may decrease the activity of IL2 and therefore should be avoided. However, patients who develop life-threatening signs or symptoms may be treated with dexamethasone until toxicity resolves or reduces to an acceptable level (generally grade 1 and 2, however must be based at the research physician's discretion).
• History of allergy to intravenously administered proteins/peptides/antibodies/ radiographic contrast media.
• HIV positive; active HIV infection, or active hepatitis B or C (assessed in local lab).
• Systemic treatment with either corticosteroid (\>10 mg daily prednisone equivalents) or Interferon alpha or immunosuppressive medications within 14 days prior to randomisation. Topical or inhalation steroids are allowed. If a patient needs to take unexpectedly immunosuppressive medication during the trial, it will be allowed but decreasing the dose as soon as possible is strongly advised.

Sponsors & Collaborators

• Maastricht University Medical Center: lead
• Academisch Ziekenhuis Maastricht: collaborator
• The Netherlands Cancer Institute: collaborator
• University Medical Center Nijmegen: collaborator
• Erasmus Medical Center: collaborator
• University Ghent: collaborator
• KU Leuven: collaborator
• Centre Oscar Lambret: collaborator
• Gasthuis Zusters Antwerpen: collaborator
• University College, London: collaborator
• Cliniques universitaires Saint-Luc- Université Catholique de Louvain: collaborator
• University Hospital Dresden: collaborator
• University Hospital Tuebingen: collaborator
• Heidelberg University: collaborator
• Catholic University of the Sacred Heart: collaborator
• Institut du Cancer de Montpellier - Val d'Aurelle: collaborator

Study Sites (15)

UCL St. Luc

Brussels, Belgium

Location

UZ Gent

Ghent, Belgium

Location

UZ Leuven

Leuven, Belgium

Location

GZA Ziekenhuizen campus Sint-Augustinus

Wilrijk, Belgium

Location

Centre Oscar Lambret Lille

Lille, France

Location

INSTITUT régional du CANCER MONTPELLIER - ICM - VAL d'AURELLE

Montpellier, France

Location

University Hospital Carl Gustav Carus

Dresden, Germany

Location

Klinikum der Universität Heidelberg

Heidelberg, Germany

Location

University Hospital Tübingen

Tübingen, Germany

Location

Fondazione Policlinico Universitario Agostino Gemelli IRCCS Università Cattolica del Sacro Cuore

Rome, Italy

Location

Academisch Ziekenhuis Maastricht (Leading Centre)

Maastricht, Limburg, 6229HX, Netherlands

Location

AVL-NKI

Amsterdam, Netherlands

Location

Radboud UMC Nijmegen

Nijmegen, Netherlands

Location

Erasmus MC

Rotterdam, Netherlands

Location

University College London Hospital

London, United Kingdom

Location

Related Publications (2)

• Olivo Pimentel V, Marcus D, van der Wiel AM, Lieuwes NG, Biemans R, Lieverse RI, Neri D, Theys J, Yaromina A, Dubois LJ, Lambin P. Releasing the brakes of tumor immunity with anti-PD-L1 and pushing its accelerator with L19-IL2 cures poorly immunogenic tumors when combined with radiotherapy. J Immunother Cancer. 2021 Mar;9(3):e001764. doi: 10.1136/jitc-2020-001764.

  PMID: 33688020 DERIVED

• Lieverse RIY, Van Limbergen EJ, Oberije CJG, Troost EGC, Hadrup SR, Dingemans AC, Hendriks LEL, Eckert F, Hiley C, Dooms C, Lievens Y, de Jong MC, Bussink J, Geets X, Valentini V, Elia G, Neri D, Billiet C, Abdollahi A, Pasquier D, Boisselier P, Yaromina A, De Ruysscher D, Dubois LJ, Lambin P. Stereotactic ablative body radiotherapy (SABR) combined with immunotherapy (L19-IL2) versus standard of care in stage IV NSCLC patients, ImmunoSABR: a multicentre, randomised controlled open-label phase II trial. BMC Cancer. 2020 Jun 15;20(1):557. doi: 10.1186/s12885-020-07055-1.

  PMID: 32539805 DERIVED

Related Links

• Website of ImmunoSABR trial

MeSH Terms

Conditions

Carcinoma, Non-Small-Cell Lung; Neoplasm Metastasis

Interventions

L19-IL2 immunocytokine; Radiation; Radiotherapy

Condition Hierarchy (Ancestors)

Carcinoma, Bronchogenic; Bronchial Neoplasms; Lung Neoplasms; Respiratory Tract Neoplasms; Thoracic Neoplasms; Neoplasms by Site; Neoplasms; Lung Diseases; Respiratory Tract Diseases; Neoplastic Processes; Pathologic Processes; Pathological Conditions, Signs and Symptoms

Intervention Hierarchy (Ancestors)

Physical Phenomena; Therapeutics

Study Officials

• Philippe Lambin, MD, PhD

  Maastricht University

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Model Details: This will be a multicentre, randomised controlled open-label phase II trial testing if the combination of (SAB)R and immunocytokine L19-IL2 improves the progression-free survival in patients with limited metastatic non-small cell lung cancer (NSCLC). The patients included in the trial will be stratified for the metastatic load (oligo; max 5 or diffuse; 6-10 metastases). After randomisation, patients will be assigned either to the experimental arm or the standard of care (SOC) arm. Depending on the metastatic load, patients with (max 5 metastases) will receive in the experimental arm SABR to all lesions followed by L19-IL2 followed by standard of care therapy. Patients with more extensive metastatic disease (6 to up to 10 metastasis) in the experimental arm will be included following first or second line treatment with a platinum doublet and receive radiotherapy (3x8 Gy) to at least one (symptomatic) lesion, followed by L19-IL2 followed by SOC.

Study Record Dates

• First Submitted: June 27, 2018
• First Posted: October 15, 2018
• Study Start: April 4, 2019
• Primary Completion: January 6, 2025
• Study Completion: January 6, 2025
• Last Updated: January 30, 2025

Record last verified: 2025-01

Locations

IT (1); GB (1); BE (4); DE (3); NL (4); FR (2)