Phase II study examining the activity of L19-IL2 immunotherapy and stereotactic ablative radiotherapy in metastatic non-small cell lung cancer

The study population consists of adult, squamous and non-squamous, non-small
cell lung cancer patients with Stage IV metastatic disease (up to 10
metastases).

• More than 10 metastatic lesions
• More than 2 brain metastatic lesions
• Two brain metastases with a cumulative diameter larger than 5 cm.
• Patients with non-infectious pneumonitis, uncontrolled thyroid disease
pleuritis, pericarditis
peritonitis carcinomatosis, severe pleuritis and pleuritis
carcinomatosis
• Patients who received live vaccines 30 days or fewer prior to
enrolment.(Patient can still participate after this is reached.)
• Patients who are already actively participating in another study
• Previous radiotherapy to an area that would be re-treated by (SAB)R resulting
in overlap of the
high dose areas
• Patients that need (maintenance) chemotherapy during ImmunoSABR in the E-arm
• Pregnancy or breast feading; it is well known that ED-B, the target of both
L19-IL2, is
expressed in a variety of fetal tissues. Furthermore, anti-PD(L)1
treatment may increase the
risk of immune-mediated disorders. Therefore it will be contra
indicated for pregnant or
lactating women.
• 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 from the first dose of study medicine
• Women of childbearing potential (WOCBP) and WOCPD partners of male
patients must be
using, from the screening to three months following the last study drug
administration and 45
months after last dose of antanti-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),
• Whole brain radiotherapy (WBRT) is not allowed, although it is accepted when
given at least 3 weeks prior to randomisation or after the treatment period.
Patients with stable brain metastases are not excluded.
• Excluded are those with (non-)infectious pneumonitis and uncontrolled thyroid
disease,. as well as infectious pericarditis, infectious pleuritis or
infectious peritonitis. Patients become eligible once treated and stable
(thyroid disease) or recovered (note: patients with a medical history of
immunotherapy induced pneumonitis grade 3 or higher are always excluded).
Patients with pericarditis carcinomatosa, pleuritis carcinomatosa or
peritonitis carcinomatosa are excluded (based on Dingemans et al, JTO 2019;
Lievens et al, R&O 2021). Patients with a small amount of pericardial, pleural
or peritoneal fluid, and no diagnosis of malignant cells in this fluid (at
least once evaluation), or with so little fluid that cytological evaluation is
not possible and/or without other findings suggestive for malignancy (i.e. no
pericardial, pleural or peritoneal thickening) are eligible
• History of immunotherapy related toxicity grade 3 or higher , except for
controlled endocrine toxicity.
• 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
L19-IL2/proteins/peptides/antibodies/ radiographic contrast media.
• HIV positive; active HIV infection, or active hepatitis B or C (assessed in
local lab). 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.
• 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.
• Prior history of organ transplant, including autologous stem cell transplant.
• Acute or sub-acute coronary syndromes within the last year, acute
inflammatory heart disease, heart insufficiency NYHA > 2, or irreversible
cardiac arrhythmias.
• 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.
• Uncontrolled hypertensive disease; (systolic blood pressure (SBP) >=160
or diastolic blood pressure (DBP) >=100 mm Hg during two measurements).
• Uncontrolled and symptomatic hypotensive disease; (systolic blood
pressure (SBP) <85 or diastolic blood pressure (DBP) <55 mm Hg during two
measurements).
• History or evidence of active autoimmune disease.
• Severe diabetic retinopathy (neoangiogenesis targeted by L19 outside
the tumour).
• Major trauma, including oncologic surgery, but excluding smaller
procedures like the placement of porth-à-cath or surgical biopsy, within 4
weeks prior to randomisation (neoangiogenesis targeted by L19 outside a tumour).
• Any underlying mental, medical or psychiatric condition which in the
opinion of the investigator will make administration of study drug hazardous or
hinder the interpretation of study results. Unstable or serious concurrent
uncontrolled medical conditions.