Trial to Evaluate Safety and Efficacy of Vinorelbine With Metronomic Administration in Combination With Atezolizumab as Second-line Treatment for Patients With Stage IV Non-small Cell Lung Cancer

Study Overview
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Brief Summary
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The majority of patients diagnosed with advanced NSCLC are treated with platinum-doublet chemotherapy regimens, except those harboring specific oncogenic drivers such as epidermal growth-factor-receptor (EGFR) mutations or anaplastic lymphoma kinase (ALK) rearrangements. In the second-line setting, response rates remain low and median survival rarely exceeds 10 months. Over the past few years, several checkpoint inhibitors targeting programmed cell death protein-1 (PD1) or its ligand (PDL1) used as second-line therapies generated evidence of improving survival and, more recently, as first-line NSCLC treatment. Although pembrolizumab (anti-PD1) was recently approved as first-line treatment for patients with at least 50% of their NSCLC cells expressing PDL1, many patients are still not benefiting from this first-line agent. For patients with relapsed NSCLC, atezolizumab (anti-PDL1) prolonged survival compared to docetaxel in the phase II POPLAR and phase III OAK trials. Novel concepts of synergic action between immunotherapy and chemotherapy have emerged recently. However, those types of treatments are given for different durations: chemotherapy is allowed for only a short period (rarely exceeding 6 cycles), while anti-PDL1 can be continued for several months until loss of its clinical benefit. Metronomic chemotherapy is defined as low-dose and frequent chemotherapy administration, without prolonged drug-free breaks. Metronomic administration of oral vinorelbine has been tested against breast cancer and advanced refractory NSCLC. The combination could have immunostimulatory effects: induction of immunogenic cancer-cell death, enhancement of antigen presentation through dendritic cell modulation, increased cancer-cell immunogenicity, preferential depletion of regulatory T cells, modulation of myeloid-derived suppressor cells, enhancement of the cytotoxic activity of immune-effector cells.

Official Title
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Open Label Phase II Trial to Evaluate Safety and Efficacy of Vinorelbine With Metronomic Administration in Combination With Atezolizumab as Second-line Treatment for Patients With Stage IV Non-small Cell Lung Cancer

Conditions
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Non-small Cell Lung Cancer

Intervention / Treatment
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* Drug: Atezolizumab
* Drug: Vinorelbine


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Histologically confirmed NSCLC; Locally advanced and/or metastatic stage IV NSCLC (according to American Joint Committee on Cancers) or recurrent NSCLC); Patients without activating EGFR mutation or ALK rearrangement and ROS1 fusions. Subject has provided a formalin-fixed tumor-tissue sample of a tumor-lesion biopsy, either at the time of or after metastatic disease was diagnosed AND from a site not previously irradiated to assess for PDL1 status. Archived tissue may be acceptable or PDL1 status known; Progressive disease after first-line platinum-doublet-based chemotherapy according to RECIST V.1.1 with measurable lesion (RECIST V1.1); Age ≥18 years, either sex; Eastern Collaborative Oncology Group Performance status (ECOG PS) 0, 1 or 2; Life expectancy exceeds 12 weeks; No history of other malignancy within the last 5 years, except for adequately treated carcinoma in situ of the cervix or basal cell or spinocellular carcinoma of the skin; Adequate organ function, demonstrated by the following laboratory results within 3 weeks prior to teatment: Normal hepatic function: bilirubin <1.5 × normal (N), Alanine aminotransferase and Aspartate aminotransferase <2.5 × N or <5 × N if liver metastasis is present; Normal renal function (calculated creatinine clearance ≥45 mL/min); Normal calcemia; Normal hematological function (polynuclear neutrophils >1.5 G/L, platelets >100 G/L and hemoglobin>8g/dl); Women of child-bearing potential must use effective contraception; Men might be surgically sterile or accept to use an effective contraceptive procedure during and until 6 months after the treatment; Written informed consent to participate in the study Patient with social insurance Exclusion Criteria: ECOG PS >2; Known hypersensitivity to immunotherapy; Small-cell lung cancer, bronchioloalveolar cancer, neuroendocrine cancer; Tumor harbors EGFR-sensitizing (activating) mutations or ALK translocations or ROS1 fusions and that justify treatment with targeted therapy ; Chemotherapy, hormonotherapy, immunotherapy or tyrosine-kinase inhibitors within the past 4 weeks prior to treatment with the trial drug; Radiotherapy (except bone or brain) within the past 3 months prior to baseline imaging; Medical contraindication to oral vinorelbine; Persistence of clinical adverse events with a grade > 2 related to prior treatment; Active brain metastases (e.g. stable for <4 weeks, no adequate previous radiotherapy, symptomatic, requiring anticonvulsants or corticosteroids) Concurrent radiotherapy, except for palliative bone irradiation. Other concurrent severe illnesses (congestive heart failure, unstable angina, significant arrhythmia or myocardial infarction <12 months before study entry); Active or prior documented autoimmune or inflammatory disorders; Active B hepatitis, HIV infection …; Psychiatric or neurological disorders preventing the patient from understanding the nature of the trial; Grade-3 peripheral neuropathy; Uncontrolled infection; Interstitial lung disease or pneumonitis requiring steroid management; Corticosteroid therapy exceeding 10 mg/day; Other severe organic disorders not allowing inclusion in the trial; Malabsorption syndrome; Pregnancy or breast-feeding; Follow-up not possible; and incarcerated or institutionalized patients.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Interventional Model Description: Atezolizumab will be administered of 1200 mg on day 1 of each 21-day cycle with IV infusions . Vinorelbine at the dose of 40 mg per days will be administered on days 1, 3 and 5 of each week of the 21-day cycle.
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Atezolizumab associated with vinorelbine<br>Atezolizumab will be administered with IV infusions. The first one will be a 60-min IV infusion; the subsequent infusions will last 30 minutes when well-tolerated at the dose of 1200 mg on day 1 of each 21-day cycle. Vinorelbine capsules are taken orally on days 1, 3 and 5 of each week of the 21-day cycle. Vinorelbine will be administered at the dose of 40 mg per day on days 1, 3 and 5 of each week of the 21-day cycle. In case of toxicity, the dose will be decreased to 30 mg. | Drug: Atezolizumab<br>* Atezolizumab in IV infusions<br>Drug: Vinorelbine<br>* Vinorelbine capsules<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Occurrence of death or progression of the disease | To evaluate the occurrence of death or progression of the disease | 4 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Emergence of adverse events (Safety and tolerability) | To evaluate the safety outcomes, tolerability, adverse events frequency | 12 months | 
| Occurrence of death | To evaluate the occurrence of death over 12 months of follow-up | 12 months | 
| Objective Response Rate | To evaluate the objective Response Rate and Disease Control Rate | 4 months | 
| Following of the quality of life | The scale EuroQol 5 dimensions (EDQ5) is used to evaluate the quality of life. The EQ-5D scale is a standardised measure of health status to provide a simple, generic measure of health for clinical and economic appraisal, whih is divided by the EQ-5D descriptive system (mobility, self care, usual activities, pain/discomfort, anxiety/depression) and the EQ Visual Analogue scale (EQ VAS). Each dimension has 5 levels (no problems, slight problems, moderate problems, severe problems, and extreme problems). | 12 months | 
| Following of the quality of life | The EORTC QLQ-C30 is a questionnaire with 30 questions developed to assess the quality of life of cancer patients. An essential aspect of the modular approach to QOL assessment adopted by the EORTC Quality of Life Group is the development of modules specific to tumour site, treatment modality, or a QOL dimension, to be administered in addition to the core questionnaire (EORTC QLQ-C30). | 12 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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immunotherapy, second line of chemotherapy