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

NCT03705403

Description:

This will be a phase II trial testing if the combination of stereotactic body radiation therapy (SBRT) and L19-IL2 improves 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 stereotactic body radiotherapy to all metastatic sites (max 3 sites irradiated) and patients with diffuse metastatic lesions (max 10) will receive radiotherapy to max 3 sites. In the experimental arm, immunotherapy will be given after irradiation.

Related Conditions:
  • Non-Small Cell Lung Carcinoma
Recruiting Status:

Not yet recruiting

Phase:

Phase 2

Trial Eligibility

Document

Title

  • Brief Title: IMMUNOtherapy and Stereotactic ABlative Radiotherapy (IMMUNOSABR) a Phase II Study
  • Official Title: Phase II Study Examining the Activity of L19-IL2 Immunotherapy and Stereotactic Ablative Radiotherapy in Metastatic Non-small Cell Lung Cancer

Clinical Trial IDs

  • ORG STUDY ID: UM2018IMMUNOSABR2RLPL
  • NCT ID: NCT03705403

Conditions

  • NSCLC Stage IV
  • Metastatic Disease

Interventions

DrugSynonymsArms
DarleukinL19 - IL2Experimental treatment

Purpose

This will be a phase II trial testing if the combination of stereotactic body radiation therapy (SBRT) and L19-IL2 improves 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 stereotactic body radiotherapy to all metastatic sites (max 3 sites irradiated) and patients with diffuse metastatic lesions (max 10) will receive radiotherapy to max 3 sites. In the experimental arm, immunotherapy will be given after irradiation.

Detailed Description

      IMMUNOSABR will include 130 patients. In this single stage controlled randomised open-label
      phase II trial, we aim to demonstrate an absolute increase in progression-free survival
      (primary endpoint). PFS will be determined as the time between randomisation and disease
      progression, according to RECIST 1.1, death due to any cause or last patient contact alive
      and progression-free. Patients will be randomized between control (no immunocytokine) and
      experimental arms (with immunocytokine L19-IL2) in a 1:1 ratio. The accrual period will be 29
      months (or 2.41 years), and the minimum follow-up will be 18 months (or 1.5 years), making
      the total study duration 47 months. Comparison between control and experimental arms will be
      made using the Log-Rank statistic. This test for superiority will be one-sided with the
      desired type I error of 0.10 and power of 0.90.

      Patients enrolled in the trial will be randomised into the control arm (C-arm) or
      experimental arm (E-arm).

        -  C-arm: Standard of Care (SOC) according to the local and national guidelines: (wait and
           see or surgery and/or chemotherapy and/or standard (symptomatic) radiotherapy and/or
           Stereotactic ABlative Radiotherapy (SABR), oligometastatic disease.

        -  E-arm: Standard of Care (SOC) SABR (oligometastatic disease) or radiotherapy (diffuse
           disease) + L19-IL2 up to 6 cycles

      The expected 1.5-year PFS is 15% in the C-arm and 35% in the E-arm. The study is therefore
      powered to test for a difference (minimal 20%) in PFS at 1.5 years after randomisation. The
      null hypothesis (H0) is that there is no difference in PFS between C-arm and E-arm. This
      results in a sample size of 124 patients evenly divided over two arms with 62 patient per
      arm. Considering a dropout rate of 5% from current experience, the actual amount of patients
      will be 65 per arm or 130 in total.

      Simple univariate comparisons of outcome and toxicity will be made between both treatment
      arms, using Chi-square tests for categorical data and independent samples t-tests for scale
      data. Secondary study parameter(s): Overall survival (OS) will be assessed using survival
      tables and Kaplan-Meier curves. PFS and OS will be calculated from the day of randomisation.
      The abscopal response, which can only be measured in the patients with diffuse metastasis
      (with at least one non-irradiated target lesion) will be measured as the best response
      between experimental and control-arms using RECIST 1.1. Quality of life " EORTC quality of
      life questionnaire (QLQ) C30 v3.0, QLQ Lung Cancer 13 (LC13) and EuroQol 5 dimensions (EQ5D)
      questionnaires" will be recorded at regular intervals see section 5.1.2.2 and table 2a+b.
      Average changes in quality of life will be reported regarding absolute differences in scores,
      and also regarding minimally clinically relevant changes.
    

Trial Arms

NameTypeDescriptionInterventions
ControlActive ComparatorStandard 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)
    Experimental treatmentExperimentalStandard of Care (SOC SABR (oligometastatic disease) or radiation therapy (diffuse disease) + L19-IL2 up to 6 cycles (Darleukin)
    • Darleukin

    Eligibility Criteria

            Inclusion Criteria:
    
            Oligometastatic disease (≤3 metastasis)
    
            In order to be eligible to participate in this study, a subject must meet all of the
            following criteria:
    
              -  Histological confirmed limited metastatic adult NSCLC patients, regardless of the
                 Programmed Death-Ligand 1 (PD-L1) status.
    
                   -  Maximum of 3 metastatic lesions, maximum one brain lesion is allowed
    
                        -  Positron Emission Tomograph (PET)-CT whole body and CT-brain or MRI brain
                           evaluation must be available no older than 6 weeks before randomisation.
    
                   -  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.
    
              -  Previous treatment:
    
                   -  Prior treatments are allowed but must be discontinued for at least 4 weeks before
                      randomisation.
    
              -  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 > or equal to 1.0 x 109 /L, platelet count > or equal to 100 x 109/L, no
                 anaemia requiring blood transfusion or erythropoietin;
    
              -  Adequate hepatic function: 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;
    
              -  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: Women of childbearing potential
                 (WOCBP) must be using, from the screening to six months following the last study drug
                 administration, effective contraception methods, 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) Signed and
                 dated written informed consent.
    
            Diffuse metastatic disease (up to 10 metastasis)
    
            In order to be eligible to participate in this study, a subject must meet all of the
            following criteria:
    
              -  Histological confirmed limited metastatic adult NSCLC patients, regardless of the
                 PD-L1 status.
    
                   -  Between 4 and 10 metastatic lesions, maximum two brain lesions are allowed
    
                        -  CT thorax-(upper) abdomen-brain within 4 weeks prior to randomisation as
                           baseline investigation.
    
                   -  Controlled disease (i.e. no progressive disease according to RECIST 1.1)
                      following primary platinum-based chemotherapy, with 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:
    
                   -  Patient inclusion is allowed from 4 weeks to 8 weeks following the last
                      platinum-based chemotherapy infusion (first line or second line). In case of
                      maintenance chemotherapy, this therapy will only be started after the end of the
                      L19-IL2 treatment Patients receiving second-line platinum-based chemotherapy
                      following primary treatment with a PD-(L)1 inhibitor is allowed.
    
              -  Age of 18 years or older.
    
              -  World Health Organization (WHO) performance status 0-1;
    
              -  Adequate bone marrow function : Absolute Neutrophil Count (ANC) of > or equal to 1.0 x
                 109 /L, platelet count > or equal to 100 x 109/L, no anaemia requiring blood
                 transfusion or erythropoietin;
    
              -  Adequate hepatic function: 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: creatinine clearance of at least 40 ml/min;
    
              -  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: Women of childbearing potential (WOCBP) must be
                 using, from the screening to six months following the last study drug administration,
                 effective contraception methods, 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)
    
              -  Signed and dated written informed consent
    
            Exclusion Criteria:
    
            For both groups; oligometastatic disease and diffuse metastatic disease
    
            A potential subject who meets any of the following criteria will be excluded from
            participation in this study:
    
              -  NSCLC with targetable mutations or gene amplifications or rearrangements.
    
              -  More than 10 metastatic lesions
    
              -  SABR to more than one brain metastasis or whole brain radiotherapy (WBRT) is not
                 allowed within the experimental arm, 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;
    
              -  Patients with progressive disease following first line or second line chemotherapy.
    
              -  More than 6 cycles of previous chemotherapy.
    
              -  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.
    
              -  History of allergy to intravenously administered proteins/peptides/antibodies;
    
              -  Contraindication for IV contrast
    
              -  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.
    
              -  Systemic treatment with either corticosteroid (>10 mg daily prednisone equivalents) or
                 other 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.
    
              -  Acute or sub-acute coronary syndromes within the last year, acute inflammatory heart
                 disease, heart insufficiency NYHA > 2, or irreversible cardiac arrhythmias;
    
              -  An 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. (LVEF
                 measurements dating back up to 8 weeks from the screening will be acceptable in the
                 absence of intercurrent use of potentially cardiotoxic treatment or cardiac medical
                 history).
    
              -  Uncontrolled hypertensive disease; (systolic BP (SBP) ≥160 or diastolic BP ≥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 breastfeeding; it is well known that ED-B, the target of both L19IL2, is
                 expressed in a variety of fetal tissues. Therefore, it will be contra-indicated for
                 pregnant or lactating women
          
    Maximum Eligible Age:N/A
    Minimum Eligible Age:18 Years
    Eligible Gender:All
    Healthy Volunteers:No

    Primary Outcome Measures

    Measure:Progression-free survival
    Time Frame:18 months after randomization of the last patient
    Safety Issue:
    Description: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.

    Secondary Outcome Measures

    Measure:Overall survival
    Time Frame:18 months after randomization of the last patient
    Safety Issue:
    Description:Assesment of the overall survival of the patient cohort.
    Measure:Change in score of The EORTC quality of life questionnaire (QLQ) core module (C30)
    Time Frame:baseline and at 3, 6, 9, 12, 15, 18, 21, 24 months after treatment
    Safety Issue:
    Description:The EORTC QLQ assesses health-related QoL of cancer patients; it consists of 30 items and covers 9 domains + 6 single symptoms. There are 5 functional scales: physical, role functioning, cognitive, emotional, social; 3 symptom scales: fatigue, pain, nausea + vomiting; a global health and QoL scale, and 6 single items. Each item has four response alternatives: 1) not at all, 2) a little 3) quite a bit 4) very much (score 1-4 with range 3); except for the global health-status/quality of life scale, which has options ranging from 1) very poor to 7) excellent (score 1-7, range 6). Answers are combined into dimensions and scores are linearly transformed into a score of 0 to 100 according to the scoring manual of the EORTC QoL group. For functional and global QoL scales, higher scores mean better level of functioning. For symptom-oriented scales, a higher score means more severe symptoms. Scores are reported as mean and standard deviation. Scores will be used in multilevel-analysis.
    Measure:Change in score of The EORTC quality of life questionnaire (QLQ) - Lung cancer module (LC13)
    Time Frame:baseline and at 3, 6, 9, 12, 15, 18, 21, 24 months after treatment
    Safety Issue:
    Description:The EORTC QLQ-LC13 The Lung Cancer Module is a supplementary questionnaire module to be employed in conjunction with the QLQ-C30. The QLQ-LC13 incorporates one multi-item scale to assess dyspnoea, and a series of single items assessing pain, coughing, sore mouth, dysphagia, peripheral neuropathy, alopecia, and haemoptysis. All items are scored 1 to 4, giving range = 3. After linear transformation scores range from 0 to100. A high score represents a high level of symptomatology or problems.
    Measure:Change in score of The Euro Quality of Life - 5 dimensions - 5 levels (EQ-5D-5L)
    Time Frame:baseline and at 3, 6, 9, 12, 15, 18, 21, 24 months after treatment
    Safety Issue:
    Description:EQ-5D-5L is a standardized instrument developed by the EuroQol Group as a measure of general health-related quality of life that can be used in a wide range of health conditions and treatments. The descriptive system comprises five dimensions: mobility, self-care, usual activities, pain/discomfort and anxiety/depression. Each dimension has 5 levels: no problems, slight problems, moderate problems, severe problems and extreme problems (score 1-5). The scores for the five dimensions are combined into a 5-digit number that describes the patient's health state.
    Measure:Change in score of The Euro Quality of Life (EQ) visual analogue scale (VAS)
    Time Frame:baseline and at 3, 6, 9, 12, 15, 18, 21, 24 months after treatment
    Safety Issue:
    Description:The EQ VAS records the patient's self-rated health on a vertical visual analogue scale from 0-100. This can be used as a quantitative measure of health outcome that reflects the patient's own judgement.
    Measure:Change in out of field radio-immune (OFRI) response
    Time Frame:at 3, 6, 9, 12, 15, 18, 21, 24 months after treatment
    Safety Issue:
    Description:To assess the occurrence of an out of field radio-immune (OFRI) response, with a scan. Assessment will be based on the RECIST criteria.
    Measure:Immunoresponse blood biomarkers by enzyme-linked immunosorbent assay (ELISA)
    Time Frame:baseline and at 3, 6 and 9 months after treatment
    Safety Issue:
    Description:To perform correlative biomarker studies related to treatment response immunoresponse blood biomarkers will be measured: osteopontin (OPN), carbonic anhydrase IX (CA-IX)], interleukin-6 (IL-6), interleukin-8 (IL-8), C-reactive protein (CRP), carcinoembryonic antigen (CEA), cytokeratin fragment 21-1 (Cyfra 21-1), alpha-2-macroglobulin (α2M), serum interleukin-2 receptor (sIL2r), toll-like receptor 4 (TLR4), vascular endothelial growth factor (VEGF), extradomain-B fibronectin (EDB). This part of the study is exploratory.

    Details

    Phase:Phase 2
    Primary Purpose:Interventional
    Overall Status:Not yet recruiting
    Lead Sponsor:Maastricht University

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