The trial will consist of one cohort of adult patients with Stage IV metastatic NSCLC

Phase 1

Conditions: The trial will consist of one cohort of adult patients with Stage IV metastatic NSCLC
MedDRA version: 20.0Level: LLTClassification code 10025044Term: Lung cancerSystem Organ Class: 100000004864
Therapeutic area: Diseases [C] - Cancer [C04]

Registration Number: EUCTR2018-002583-11-GB

Lead Sponsor: Maastricht University Medical Centre

Brief Summary: Not available

Detailed Description: Not available

Recruitment & Eligibility

Status: Authorised-recruitment may be ongoing or finished

Sex: All

Target Recruitment: 126

Inclusion Criteria

A.Oligometastatic disease (=5 metastasis):
In order to be eligible to participate in this study, a subject must meet all of the following criteria:
1.Histological/Cytological confirmed limited metastatic adult NSCLC patients, regardless of the PD-L1 status.
oMax. of 5 metastatic lesions, max. 2 brain lesions with a total cumulative diameter of 5 cm 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 < randomisation
?If a patient has unclear lesions in the liver or brain an MRI would be advised following the ESMO guidelines.
oIn 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, it is according to the decision of the local multidisciplinary tumour board whether the patient has an M1 disease or not.
2.Previous treatment: Prior cancer treatments are allowed but must be discontinued for at least 4 weeks < 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
3.Age of 18 years or older.
4.WHO performance status 0-1;
5.Adequate bone marrow function (evaluated in the local lab): Absolute Neutrophil Count (ANC) of > or equal to 1.0 x 109 /L, platelet count > or equal to 100 x 109/L, Hb greater or equal 6.0 mmol/L (or 9.67 g/dL) (it is allowed to give a blood transfusion if Hb is initially too low;
6.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);
7.Adequate renal function (evaluated in the local lab): creatinine clearance of at least 40 ml/min;
8.The patient is capable of complying with study procedures; 9.Life expectancy of at least 12 weeks;
10.Negative serum pregnancy test for women of childbearing potential (WOCBP).
11.Ability to comply with contraception requirements:
Non-sterilised, sexually active male patient with a female partner who is of child-bearing age, must use two acceptable birth control methods like a condom combined with spermicidal cream or gel, and a partner who is WOCBP must use effictive contraception as defined for WOCBP who are participants in the study as per the next paragraph. From the first dose of study medicine, during the study and at least up to 12 weeks after the last administration of the study medicine and up to 5 months after the last dose of the medicine with anti-PDL)1 as an action mechanism (if you get this product besides the study medicine), as an addition to the use, by the female partner, of as described in the following section:
Women of childbearing potential (WOCBP) and WOCBP partners of male patients must be using, from the screening to three months following the last study drug administration and 5 months after last dose of anti-PD(L)1 maintenance treatment, effective contraception methods, (a) IUD (IUD) or intrauterine hormone delivery system (IUS), b) combined (with estrogen and progesterone) hormonal contraception associated with ovulation inhibition (oral, intravaginal, transdermal), c) hormonal contraception with progesterone only associated with ovulation inhibition (oral, injectable, implantable). Reference: http://www.hma.eu/fileadmin/dat

Exclusion Criteria

For both groups; oligometastatic disease and poly-metastatic disease: A potential subject who meets any of the following criteria will be excluded from participation in this study:
1.More than 10 metastatic lesions
2.More than 2 brain metastatic lesions
3.Two brain metastases with a cumulative diameter larger than 5 cm
4.Patients with non-infectious pneumonitis, uncontrolled thyroid disease, pleuritis, pericarditis and peritonitis carcinomatosis. Or other mild/serious infection at screening that need antibiotic therapy (First treat infection, so patient can still participate after it is cleared.)
5.Patients who are already actively participating in another study.
6.Patients who need simultaneous radiation on the primary tumour and metastatic lesion(s). For these patients it might be an option to irradiate the primary tumour first although this is not mandatory for this study. There must be minimal four weeks between the last reatment and randomisation.
7.Wole 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.
8.Previous radiotherapy to an area that would be re-treated by (SAB)R, resulting in overlap of the high dose areas;
9.Maintenance therapy with Anti-PD(L)1 treatment combined with chemotherapy is not allowed during treatment ((SAB)R and L19-IL2 cycles).
10.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); 11.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)..
12.History of allergy to intravenously administered proteins/peptides/antibodies/radiographic contrast media;
13.HIV positive; active HIV infection, or active hepatitis B or C (assessed in local lab).
o?For HBV serology: the determination of HBsAg, anti-HBsAg-Ab and anti-HBCAg-Ab is required. In patients with serology documenting previous exposure to HBV (i.e., anti-HBs Ab with no history of vaccination and/or anti-HBc Ab), negative serum HBV-DNA is required. For HCV: HCV RNA or HCV antibody test. Subjects with a positive test for HCV antibody but no detection of HCV RNA indicating no current infection are eligible.
14.Systemic treatment with either corticosteroid (>10 mg daily prednisone equivalents) or Interferon aplpha 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.
15.Prior history of organ transplant, including autologous stem cell transplant.
16.Acute or sub-acute coronary syndromes within the last year, acute inflammatory heart disease, heart insufficiency NYHA > 2, or irreversible cardiac arrhythmias;
17.A known impaired cardiac function defined as left ventricular ejection fraction (LVEF) < 50 % (or below the study site's lower limit of normal) as measured by MUGA or ECHO.
18.Uncontrolled hypertensive disease; (systolic BP

Study & Design

Study Type: Interventional clinical trial of medicinal product

Study Design: Not specified

Primary Outcome Measures

Name	Time	Method
Main Objective: The main objective of the trial is to test if the combination of (SAB)R and the immunocytokine L19-IL2 has clinical meaningful activity in patients with limited metastatic non-small cell lung cancer (NSCLC): (=10 sites, WHO 0-1). The expected activity is a systemic immune response preventing disease progression and resulting in an improvement of progression-free survival (PFS) after 1.5 years after randomisation, compared to the standard of care.;Secondary Objective: •PFS for 5 years<br>•Assessment of the overall survival for 5 years<br>•Toxicity<br>•Quality of Life<br>•To assess the occurrence of an Out of Field Radio-Immune (OFRI) response<br>•To assess the occurrence of an In Field Radio-Immune (IFRI) response <br>;Primary end point(s): Primary endpoint: <br>•Progression Free Survival (PFS) at 1.5 years after randomisation compared to the Standard of care<br>;Timepoint(s) of evaluation of this end point: at the end of the study

Secondary Outcome Measures

Name	Time	Method
Secondary end point(s): Secondary endpoints:<br>•PFS<br>•Overall survival<br>•Toxicity<br>•Quality of Life<br>•Out of Filed Radio-Immune (OFRI) response.<br>•In of Filed Radio-Immune (IFRI) response<br>;Timepoint(s) of evaluation of this end point: •PFS at 5 years after randomisation<br>•Overall survival at 5 years after randomisation<br>•Toxicity at 1.5 years after randomisation<br>•QOLQ at 1.5 years after randomisation<br>•The occurrence of OFRI / the abscopal effect using imaging, at 1.5 years after randomisation<br>•The occurrence of an IFRI response, at 1.5 years after randomisation.<br><br>

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