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IMMUNOtherapy and Stereotactic ABlative Radiotherapy (IMMUNOSABR) a Phase II Study (IMMUNOSABR2)

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ClinicalTrials.gov Identifier: NCT03705403
Recruitment Status : Not yet recruiting
First Posted : October 15, 2018
Last Update Posted : October 15, 2018
Sponsor:
Collaborators:
Academisch Ziekenhuis Maastricht
KU Leuven
Catholic University of the Sacred Heart
The Netherlands Cancer Institute
University Ghent
Cliniques universitaires Saint-Luc- Université Catholique de Louvain
Centre Oscar Lambret
University Hospital Tuebingen
University College, London
University Hospital Dresden
University Medical Center Nijmegen
Information provided by (Responsible Party):
Maastricht University

Brief Summary:

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.


Condition or disease Intervention/treatment Phase
NSCLC Stage IV Metastatic Disease Drug: Darleukin Radiation: Radiation Phase 2

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.


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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 130 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Intervention Model Description: This will be a multicentre, randomised controlled open-label phase II trial testing if the combination of (SAB)R and immunocytokine L19-IL2 improves the progression-free survival in patients with limited metastatic non-small cell lung cancer (NSCLC). The patients included in the trial will be stratified for the metastatic load (oligo; max 3 or diffuse; 4-10 metastases). After randomisation, patients will be assigned either to the experimental arm or the standard of care (SOC) arm. Depending on the metastatic load, patients with (max 3 metastases) will receive in the experimental arm SABR to all lesions followed by L19-IL2 followed by standard of care therapy. Patients with more extensive metastatic disease (4 to up to 10 metastasis) in the experimental arm will be included following first or second line treatment with a platinum doublet and receive radiotherapy (3x8 Gy) to at least one (symptomatic) lesion, followed by L19-IL2 followed by SOC.
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Phase II Study Examining the Activity of L19-IL2 Immunotherapy and Stereotactic Ablative Radiotherapy in Metastatic Non-small Cell Lung Cancer
Estimated Study Start Date : December 1, 2018
Estimated Primary Completion Date : December 1, 2021
Estimated Study Completion Date : June 1, 2023

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
Active Comparator: Control
Standard 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)
Radiation: Radiation
Radiotherapy
Other Name: Radiotherapy

Experimental: Experimental treatment
Standard of Care (SOC SABR (oligometastatic disease) or radiation therapy (diffuse disease) + L19-IL2 up to 6 cycles (Darleukin)
Drug: Darleukin
The product name refers to the molecule structure, in fact, L19-IL2 is a recombinant fusion protein composed of two moieties: L19, a human monoclonal antibody fragment in the single chain Fv (scFv) format, bound via a flexible linker to IL2, the human cytokine Interleukin-2.
Other Name: L19 - IL2

Radiation: Radiation
Radiotherapy
Other Name: Radiotherapy




Primary Outcome Measures :
  1. Progression-free survival [ Time Frame: 18 months after randomization of the last patient ]
    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 :
  1. Overall survival [ Time Frame: 18 months after randomization of the last patient ]
    Assesment of the overall survival of the patient cohort.

  2. 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 ]
    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.

  3. 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 ]
    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.

  4. 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 ]
    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.

  5. 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 ]
    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.

  6. Change in out of field radio-immune (OFRI) response [ Time Frame: at 3, 6, 9, 12, 15, 18, 21, 24 months after treatment ]
    To assess the occurrence of an out of field radio-immune (OFRI) response, with a scan. Assessment will be based on the RECIST criteria.

  7. Immunoresponse blood biomarkers by enzyme-linked immunosorbent assay (ELISA) [ Time Frame: baseline and at 3, 6 and 9 months after treatment ]
    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.



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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Gender Based Eligibility:   Yes
Gender Eligibility Description:   trying to include 50% M/F in each group
Accepts Healthy Volunteers:   No
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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03705403


Contacts
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Contact: Cary Oberije, PhD +31(0)43 3883549 c.oberije@maastrichtuniversity.nl
Contact: Lieverse Relinde, MD relinde.lieverse@maastrichtuniversity.nl

Locations
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Netherlands
Academisch Ziekenhuis Maastricht Not yet recruiting
Maastricht, Limburg, Netherlands, 6229HX
Contact: Anne-Marie Dingemans, MD, PhD         
Sponsors and Collaborators
Maastricht University
Academisch Ziekenhuis Maastricht
KU Leuven
Catholic University of the Sacred Heart
The Netherlands Cancer Institute
University Ghent
Cliniques universitaires Saint-Luc- Université Catholique de Louvain
Centre Oscar Lambret
University Hospital Tuebingen
University College, London
University Hospital Dresden
University Medical Center Nijmegen
Investigators
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Principal Investigator: Philippe Lambin, MD, PhD Maastricht University

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Responsible Party: Maastricht University
ClinicalTrials.gov Identifier: NCT03705403     History of Changes
Other Study ID Numbers: UM2018IMMUNOSABR2RLPL
First Posted: October 15, 2018    Key Record Dates
Last Update Posted: October 15, 2018
Last Verified: June 2018
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Undecided

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Additional relevant MeSH terms:
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Neoplasm Metastasis
Neoplastic Processes
Neoplasms
Pathologic Processes
Interleukin-2
Antineoplastic Agents
Analgesics, Non-Narcotic
Analgesics
Sensory System Agents
Peripheral Nervous System Agents
Physiological Effects of Drugs