Small Cell Lung Carcinoma Trial With Nivolumab and IpiliMUmab in LImited Disease
- Conditions
- Limited Stage Small Cell Lung CancerSmall Cell Lung Cancer
- Interventions
- Registration Number
- NCT02046733
- Lead Sponsor
- ETOP IBCSG Partners Foundation
- Brief Summary
Despite the fact that the majority of the patients with limited disease SCLC will respond very well to the standard treatment, a great proportion will relapse within 12 - 24 months.
Several studies in patients with lung cancer suggested a possible favourable association between the increased presence of immunologically active cells in the tumour and survival. Nivolumab and ipilimumab are proteins, which help your immune system to attack and destroy cancer cells by your immune cells. Early clinical trials with nivolumab and ipilimumab have shown activity in a broad range of cancers, including SCLC.
The aim of the current study is to investigate the efficacy (how well the treatment works) and tolerability (how severe the side effects are) of the standard treatment (chemotherapy and radiotherapy) alone, compared with the standard treatment followed by nivolumab and ipilimumab in patients with limited SCLC.
- Detailed Description
At the time of diagnosis, 30% of patients with small cell lung carcinoma (SCLC) will have limited stage disease, now called stage I-IIIB (IASLC). The outcome of limited disease SCLC is still poor, with a median survival of 16 to 24 months with current forms of treatment and only 15-25% long term survivors.
Combining chemotherapy and thoracic radiotherapy is the standard treatment approach in limited-stage SCLC with a combination of platinum compounds (cis- or carboplatin) and etoposide and cisplatin (PE) as the backbone regimen. Concurrent chemo-radiotherapy is superior to sequential treatment and early thoracic irradiation starting with first or second cycle of chemotherapy appears beneficial. Hyperfractionated accelerated radiotherapy has been shown to be more efficacious than radiotherapy given in a long overall treatment time. However, availability and routine-use of hyperfractionated radiotherapy remains a matter of debate. Therefore, in this trial, both radiotherapy schedules of accelerated twice-daily administration or once-daily radiotherapy are accepted. The choice of schedule is a stratification factor for randomisation.
The adaptive immune response is triggered via effector T-cells, antigen-presenting cells (APCs) and co-stimulatory signals mediated by T cell receptors such as CD28. The interplay of these signals results in the activation and clonal proliferation of T cells.
T-cell proliferation is tightly regulated in order to avoid autoimmunity. The balance between co-stimulatory signals mediated by CD28 and co-inhibitory signals via so called immune checkpoint receptors is crucial for the maintenance of self-tolerance and to protect tissues from damage during normal immune response. After activation, T-cells express the immune checkpoint receptors cytotoxic T-lymphocyte antigen-4 (CTLA-4) and programmed cell death protein 1 (PD-1).
CTLA-4- and PD-1 expressing T-cells play a critical role in maintaining self-tolerance but are also responsible for non-responsiveness to tumour antigens. Cancer cells escape from im-mune surveillance by expressing immune checkpoint receptors. The goal of immune check-point inhibitor therapies is not to activate the immune system to attack particular targets on tumour cells, but rather to remove inhibitory pathways that block effective antitumour T cell responses.
Ipilimumab is a monoclonal antibody that binds to CTLA-4 and inhibits the interactions with the ligands B7.1 and B7.2, Nivolumab is a monoclonal antibody that targets PD-1. Engagement of PD-1 by its natural ligands, PD-L1 and PD-L2, results in an inhibition of T cell proliferation, survival and cyto-kine secretion. Nivolumab abrogates this interaction between PD-1 and its ligands.
The two antibodies, nivolumab and ipilimumab, do not only target different immune cell receptors, they also regulate distinct inhibitory pathways and have therefore non-overlapping mechanisms of action. Anti-CTLA-4 therapies seem to drive T-cells into tumours, resulting in an increased number of intratumour T-cells and a concomitant increase in IFN-y. This in turn can induce the expression of PD-L1 in the tumour microenvironment, with subsequent inhibition of antitumour T-cell responses, but may also increase the chance of benefit from anti-PD-1 and anti-PD-L1 therapies. A combination treatment with anti-CTLA-4 (e.g. ipili-mumab) plus anti PD-1 (e.g. nivolumab) or anti-PD-L1 antibodies should enable the creation of an immunogenic tumour microenvironment with subsequent clinical benefit for patients.
Nivolumab monotherapy has been approved for the treatment of advanced melanoma (FDA, EMA, and Japan) and previously treated squamous NSCLC (FDA, positive CHMP opin-ion). Nivolumab and ipilimumab improved PFS compared to nivolumab or ipilimumab alone in a study in melanoma (CA209067).
In a randomised open-label phase I/II trial (CheckMate 032), evaluating nivolumab with or without ipilimumab in pretreated SCLC patients with progressive disease and sensitive or refractory to platinum based chemotherapy, based on an interim analysis a response rate of 33% and disease stabilisation in 22% was observed for the combination of nivolumab and ipilimumab compared to 18% response rate and 20% stable disease with nivolumab mono-therapy.
Both, nivolumab monotherapy and nivolumab plus ipilimumab combination treatment were tolerable for the treatment of SCLC, and no new safety profile was identified compared to the profile of nivolumab with or without ipilimumab in other anti-cancer therapies.
Nivolumab plus ipilimumab will be administered as a consolidation treatment after comple-tion of a standard treatment including chemo-radiotherapy and prophylactic cranial irradia-tion (PCI).
Recruitment & Eligibility
- Status
- COMPLETED
- Sex
- All
- Target Recruitment
- 222
Not provided
Not provided
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- PARALLEL
- Arm && Interventions
Group Intervention Description Nivolumab + Ipilimumab Ipilimumab - Induction: Nivolumab at a dose of 1 mg/kg i.v. followed (on the same day) by Ipilimumab at a dose of 3 mg/kg i.v. once every 3 weeks, 4 cycles - Maintenance: Nivolumab 240 mg i.v. once every 2 weeks, for a maximum of 12 months from start of maintenance Nivolumab + Ipilimumab Nivolumab - Induction: Nivolumab at a dose of 1 mg/kg i.v. followed (on the same day) by Ipilimumab at a dose of 3 mg/kg i.v. once every 3 weeks, 4 cycles - Maintenance: Nivolumab 240 mg i.v. once every 2 weeks, for a maximum of 12 months from start of maintenance
- Primary Outcome Measures
Name Time Method Progression-free Survival (PFS) From the date of randomization until documented progression (PD) according to RECIST v1.1 or death from any cause (whichever occurred first), up to 4.5 years. Defined as the time from the date of randomization until documented progression or death, if progression is not documented. Censoring for PFS occurs at the last tumor assessment.
Assessment of Progressive Disease (PD) based on Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.1):
Target lesions: At least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on the study (this includes the baseline sum if that is the smallest on the study). In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm. Non-target lesions: Unequivocal progression of existing non-target lesions. To achieve 'unequivocal progression', there must be an overall level of substantial worsening in non-target disease such that, even in presence of SD or PR in target disease, the overall tumor burden has increased sufficiently.
The appearance of one or more new lesions is also considered as progression.
- Secondary Outcome Measures
Name Time Method Overall Survival (OS) From the date of randomization until death from any cause, up to 5.5 years. Defined as the time from the date of randomisation until death from any cause. Censoring for OS occurs at the last follow-up date.
Objective Response (OR) From randomisation to termination of trial treatment, for a maximum of 12 months from start of maintenance phase. Objective response is defined as the best overall response (complete or partial response) according to RECIST 1.1 criteria across all assessment time-points during the period from randomisation to termination of trial treatment. Of note, the determination of OR is restricted to patients who have not attained a CR during the chemo-radiotherapy phase.
Complete Response (CR): Disappearance of all target lesions, Partial Response (PR): At least a 30% decrease in the sum of diameters of target lesions taking as reference the baseline sum of diameters, Progression (PD): At least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum recorded on the trial. In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm., Stable Disease (SD): Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD taking as reference the smallest sum of diameters recorded on the trial.Time-to-treatment Failure (TTF) From the date of randomization to treatment failure for any reason, up to 4.5 years. Defined as the time from the date of randomisation to discontinuation of treatment for any reason (including progression of disease, treatment toxicity, refusal, lost to follow-up, and death). Censoring for TTF occurs at the last follow-up date.
Adverse Events Adverse events were assessed from randomization to 100 days after the last dose of study treatment, up to 4.5 years. Adverse events graded according to NCI CTCAE V4.0.
Trial Locations
- Locations (57)
Royal Hobart Hospital
🇦🇺Hobart, Australia
Hospital Universitario 12 Octubre
🇪🇸Madrid, Spain
Coffs Harbour Health Campus
🇦🇺Coffs Harbour, Australia
Riverina Cancer Centre
🇦🇺Mount Kuring-gai, Australia
Hospital Puerta de Hierro
🇪🇸Madrid, Spain
Royal Brisbane and Women's Hospital (QLD)
🇦🇺Herston, Australia
Hospital Virgen De La Salud
🇪🇸Toledo, Spain
Hospital Clínico Universitario De Valencia
🇪🇸Valencia, Spain
Royal Marsden
🇬🇧London, United Kingdom
NNSWLHD - The Tweed Hospital
🇦🇺Lismore, Australia
Bendigo Hospital
🇦🇺Bendigo, Australia
Maastro Clinic
🇳🇱Maastricht, Netherlands
Hospital Universitario Central De Asturias
🇪🇸Oviedo, Spain
Hospital De La Santa Creu I Sant Pau
🇪🇸Barcelona, Spain
Clinico San Carlos
🇪🇸Madrid, Spain
Hospital Universitario Fundacion Jimenez Díaz
🇪🇸Madrid, Spain
Pius-Hospital Oldenburg
🇩🇪Oldenburg, Germany
Krankenhaus der Barmherzigen Brüder
🇩🇪Trier, Germany
Hospital General Universitario Alicante
🇪🇸Alicante, Spain
Hospital Universitario Cruces
🇪🇸Barakaldo, Spain
Centre Hospitalier Universitaire Vaudois
🇨🇭Lausanne, Switzerland
Paris - Saint-Louis
🇫🇷Paris, France
Paris - Tenon
🇫🇷Paris, France
Thoracic Oncology Centre Munich
🇩🇪München, Germany
University Hospital Zürich
🇨🇭Zürich, Switzerland
St James' University Hospital
🇬🇧Leeds, United Kingdom
VUMC
🇳🇱Amsterdam, Netherlands
CHI
🇫🇷Toulon, France
Créteil - CHI
🇫🇷Creteil, France
Nouvel Hôpital Civil
🇫🇷Strasbourg, France
Port Macquarie Base Hospital
🇦🇺Port Macquarie, Australia
Austin Hospital
🇦🇺Melbourne, Australia
Princess Alexandra Hospital
🇦🇺Woolloongabba, Australia
Epworth HealthCare - Richmond
🇦🇺Richmond, Australia
University Hospital Gasthuisberg, KU Leuven
🇧🇪Leuven, Belgium
CHU
🇫🇷Tours, France
Avignon - Institut Sainte-Catherine
🇫🇷Avignon, France
Percy/Armées
🇫🇷Clamart, France
Caen - Centre François Baclesse
🇫🇷Caen, France
Lyon - Sud
🇫🇷Lyon, France
AP-HM
🇫🇷Marseille, France
Hôpital Louis Pradel
🇫🇷Lyon, France
Paris - Bichat
🇫🇷Paris, France
CH
🇫🇷Mulhouse, France
Orléans - CH
🇫🇷Orléans, France
CRLCC
🇫🇷Nantes, France
Nice - CRLCC
🇫🇷Nice, France
Suresnes
🇫🇷Suresnes, France
Klinikum Esslingen
🇩🇪Esslingen, Germany
LungenClinic Grosshansdorf GmbH
🇩🇪Grosshansdorf, Germany
Klinikum München-Bogenhausen
🇩🇪München, Germany
The Christie NHS Foundation Trust
🇬🇧Manchester, United Kingdom
Centre Hospitalier Général
🇫🇷Le Mans, France
Institut Gustave Roussy
🇫🇷Villejuif, France
Clermont-Ferrand
🇫🇷Clermont-Ferrand, France
Centre Hospitalier Universitaire de Montpellier
🇫🇷Montpellier, France
Universitätsklinikum Tübingen
🇩🇪Tübingen, Germany