Overview

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.

Eligibility

Inclusion criteria

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;
          -  Negative serum pregnancy test for females of childbearing potential.
          -  Signed and dated written informed consent.
          -  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 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 4 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), as defined by the
        "Recommendations for contraception and pregnancy testing in clinical trials" issued by the
        Head of Medicine Agencies' Clinical Trial Facilitation Group (www.hma.eu/ctfg.html).
        Poly-metastatic disease (6 to 10 metastases)
        • Histological confirmed limited metastatic adult NSCLC patients, regardless of the PD-L1
        status.
        A minimum of 6 and maximum of 10 metastatic lesions, maximum two brain lesion with a total
        cumulative diameter of 5cm is allowed.
        At least one measurable lesion (according to RECIST 1.1) that has no overlap with the PTV
        of the lesion subjected to radiotherapy.
        • Previous treatment: The time between the last administration of chemotherapy and the
        randomisation must be at least 4 weeks. In case of maintenance chemotherapy, this therapy
        will only be started after the study if e-arm, allowed during c-arm. In case of Anti-PD(L)1
        treatment, this is allowed in both arms, so also during L19-IL2 therapy.
          -  Age of 18 years or older;
          -  WHO performance status 0-1;
          -  Adequate bone marrow function (evaluated in the local lab): Absolute Neutrophil Count
             (ANC) of ≥ 1.0 x 109 /L, platelet count ≥ 100 x 109/L, 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;
          -  Negative serum pregnancy test for females of childbearing potential;
          -  Ability to comply with contraception requirements (see oligo)
          -  Signed and dated written informed consent.
        Exclusion criteria
          -  More than 10 metastatic lesions.
          -  More than 2 brain metastatic lesions.
          -  2 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.
          -  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).
          -  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.
          -  Pregnancy or breast feeding; it is well known that ED-B, the target of both L19IL2, 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.