E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
The trial will consist of one cohort of adult patients with Stage IV metastatic NSCLC
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E.1.1.1 | Medical condition in easily understood language |
Patients with progressive lung cancer with a maximum of 10 metastatic lesions will receive Standard Of Care combined with immunotherapy |
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E.1.1.2 | Therapeutic area | Diseases [C] - Cancer [C04] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 20.0 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10025044 |
E.1.2 | Term | Lung cancer |
E.1.2 | System Organ Class | 100000004864 |
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E.1.3 | Condition being studied is a rare disease | No |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
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). |
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E.2.2 | Secondary objectives of the trial |
• Assesment of the overall survival • Toxicity • Quality of Life • To assess the occurrence of an Out of Field Radio-Immune (OFRI) response • To assess the occurrence of an In Field Radio-Immune (IFRI) response
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
A.Oligometastatic disease (≤5 metastasis): 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. 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, it is according to the decision of the local multidisciplinary tumour board whether the patient has an M1 disease or not. 2.Previous treatment: patient inclusion is allowed from 4 w following the last chemo- and/or immunotherapy infusion (first line or second line, exc. aPD(L)1 treatment. In case of maintenance chemotherapy, this can continue during the C-arm and not allowed in the E-arm. 3. Patient received a (last gift) of live vaccine need to wait 8 weeks before they can be randomised and reciev a PD(L)1 treatment. 4.Age of 18 years or older. 5.WHO performance status 0-1; 6.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; 7.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); 8.Adequate renal function (evaluated in the local lab): creatinine clearance of at least 40 ml/min; 9.Adequate endocrine function: TSH based on local laboratory guidelines, FT4 based on local laboratory guidelines. Make sure lower/higher values are not the cause of medication (e.g. heparin i.v. amiodarone, lithium). 10.The patient is capable of complying with study procedures; 11.Life expectancy of at least 12 weeks; 12.Negative serum pregnancy test for women of childbearing potential. 13.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 definied 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). 14.Signed and dated written informed consent;
B) Poly-metastatic disease (6 to 10 metastasis) 1.Histological/Cytological confirmed limited metastatic adult NSCLC patients, regardless of the PD-L1 status. o A minimum of 6 and maximum of 10 metastatic lesions, maximum two 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 prior to randomisation. If a patient has unclear lesions in the liver or brain an MRI would be advised following the ESMO Guidelines. o at least one measurable lesion (according to RECIST 1.1) that has no overlap with the PTV of the lesion subjected to radiotherapy. 2.Previous treatment: oThe time between the last administration of chemo and/or immunotherapy (given as first or second line standard of care treatment) and the randomisation must be at least 4 weeks. 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. Inclusion criteria 3 to 14 are identical to the oligometastatic patients. |
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E.4 | Principal 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 might need antibiotic therapy. (First treat infection, so patient can still participate after it is cleared.) 5.Patients who are already actively participating in another interventional study with an investigational product. 6.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 4 weeks between last treatment and randomisation. 7.SABR to more than one brain metastasis or 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. 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 L19-IL2 / 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 (SBP) ≥160 or diastolic BP ≥100 mm Hg during two measurements) 19.Uncontrolled and symptomatic hypotensive disease; (systolic blood pressure (SBP) <85 or diastolic blood pressure (DBP) <55 mm Hg during two measurements). 20.History or evidence of active autoimmune disease; 21.Severe diabetic retinopathy (neoangiogenesis targeted by L19 outside the tumour) 22.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) 23.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 24.Pregnancy or breastfeeding; 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 24.Patients who received live vaccines 30 days or fewer prior to enrolment.
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E.5 End points |
E.5.1 | Primary end point(s) |
Primary endpoint: • Progression Free Survival (PFS) at 1.5 years after randomisation compared to the Standard of care
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
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E.5.2 | Secondary end point(s) |
Secondary endpoints: • 5 years PFS • 1,5 years and 5 years Overall survival • 1,5 years toxicity, Quality of Life, Out of Filed Radio-Immune (IFRI) response and in field Radio-Immune (IFRI) response
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
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E.6 and E.7 Scope of the trial |
E.6 | Scope of the trial |
E.6.1 | Diagnosis | No |
E.6.2 | Prophylaxis | No |
E.6.3 | Therapy | Yes |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | No |
E.6.7 | Pharmacodynamic | No |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | No |
E.6.10 | Pharmacogenetic | No |
E.6.11 | Pharmacogenomic | No |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | No |
E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | No |
E.7.1.1 | First administration to humans | No |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | No |
E.7.1.3.1 | Other trial type description | |
E.7.2 | Therapeutic exploratory (Phase II) | Yes |
E.7.3 | Therapeutic confirmatory (Phase III) | No |
E.7.4 | Therapeutic use (Phase IV) | No |
E.8 Design of the trial |
E.8.1 | Controlled | Yes |
E.8.1.1 | Randomised | Yes |
E.8.1.2 | Open | Yes |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | No |
E.8.1.5 | Parallel group | No |
E.8.1.6 | Cross over | No |
E.8.1.7 | Other | No |
E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | No |
E.8.2.2 | Placebo | No |
E.8.2.3 | Other | Yes |
E.8.2.3.1 | Comparator description |
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E.8.2.4 | Number of treatment arms in the trial | 2 |
E.8.3 |
The trial involves single site in the Member State concerned
| No |
E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
E.8.4.1 | Number of sites anticipated in Member State concerned | 3 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 11 |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | No |
E.8.6.2 | Trial being conducted completely outside of the EEA | No |
E.8.7 | Trial has a data monitoring committee | Yes |
E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
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The sponsor will notify the Ethics Committee / Competent Authority of the end of the study within 90 days. The end of the study is defined as the last patient’s last visit. |
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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 4 |
E.8.9.1 | In the Member State concerned months | |
E.8.9.1 | In the Member State concerned days | |
E.8.9.2 | In all countries concerned by the trial years | 4 |