Clinical trial NCT03801304: 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
Official title: 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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Non-small Cell Lung Cancer
Keywords: immunotherapy
second line of chemotherapy
Lead sponsor: University Hospital, Brest
Sponsor class: OTHER
Collaborators: name: Groupe Francais De Pneumo-Cancerologie
name: Roche Farma, S.A
name: Pierre Fabre Medicament
First posted: 2019-01-11
Enrollment: 80
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Intervention 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.
Primary purpose: TREATMENT

Brief summary: 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.


Eligibility criteria: 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.

Primary outcomes:
measure: Occurrence of death or progression of the disease
timeFrame: 4 months
Secondary outcomes:
measure: Emergence of adverse events (Safety and tolerability)
timeFrame: 12 months
measure: Occurrence of death
timeFrame: 12 months
measure: Objective Response Rate
timeFrame: 4 months
measure: Following of the quality of life
timeFrame: 12 months
measure: Following of the quality of life
timeFrame: 12 months
Other outcomes:
Locations:
city: Aix-en-Provence
country: France
facility: CH Aix en Provence
city: Brest
country: France
facility: CHRU de Brest - Hôpital Morvan
city: Caen
country: France
facility: CLCC Caen
city: Créteil
country: France
facility: CH de Créteil
city: La Roche Sur Yon
country: France
facility: Ch La Roche Sur Yon
city: Limoges
country: France
facility: CHU de Limoges - Hôpital DUPUYTREN
city: Meaux
country: France
facility: CH MEAUX
city: Pringy
country: France
facility: CH Pringy
city: Quimper
country: France
facility: CH Quimper
city: Rennes
country: France
facility: CHU de Rennes
city: Rouen
country: France
facility: CHU Rouen
city: Saint-Brieuc
country: France
facility: CH Saint-Brieuc
city: Toulon
country: France
facility: Hia Saint Anne
Study officials:
References:
citation: Vergnenegre A, Monnet I, Bizieux A, Bernardi M, Chiapa AM, Lena H, Chouaid C, Robinet G. Open-label Phase II trial to evaluate safety and efficacy of second-line metronomic oral vinorelbine-atezolizumab combination for stage-IV non-small-cell lung cancer - VinMetAtezo trial, (GFPCdouble dagger 04-2017). Future Oncol. 2020 Feb;16(4):5-10. doi: 10.2217/fon-2019-0730. Epub 2020 Jan 2.