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
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|
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 188.8.131.52 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.
|Study Type :||Interventional (Clinical Trial)|
|Estimated Enrollment :||130 participants|
|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)|
|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|
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)
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)
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
Other Name: Radiotherapy
- 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.
- Overall survival [ Time Frame: 18 months after randomization of the last patient ]Assesment of the overall survival of the patient cohort.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03705403
|Contact: Cary Oberije, PhD||+31(0)43 firstname.lastname@example.org|
|Contact: Lieverse Relinde, MDemail@example.com|
|Academisch Ziekenhuis Maastricht||Not yet recruiting|
|Maastricht, Limburg, Netherlands, 6229HX|
|Contact: Anne-Marie Dingemans, MD, PhD|
|Principal Investigator:||Philippe Lambin, MD, PhD||Maastricht University|