Small Cell Lung Carcinoma Trial With Nivolumab and IpiliMUmab in LImited Disease

NCT ID: NCT02046733

Last Updated: 2024-11-08

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE2
• Total Enrollment: 222 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2015-12-18
• Study Completion Date: 2022-02-01

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).

Conditions

Limited Stage Small Cell Lung Cancer; Small Cell Lung Cancer

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

Nivolumab + 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

Group Type: EXPERIMENTAL

Ipilimumab

Intervention Type: DRUG

Induction phase: i.v. 3 mg/kg, once every 3 weeks × 4 cycles, to start within 6-8 weeks (42-56 days) from start of chemotherapy cycle 4, and not more than 2 weeks (14 days) after the date of randomisation)

Nivolumab

Intervention Type: DRUG

Induction phase: Nivolumab i.v. 1 mg/kg, once every 3 weeks × 4 cycles, to start within 6-8 weeks (42-56 days) from start of chemotherapy cycle 4, and not more than 2 weeks (14 days) after the date of randomisation) Maintenance Phase: Nivolumab 240 mg i.v once every 2 weeks for a maximum of 12 months from start of maintenance (the first dose of maintenance nivolumab will be administered 3 weeks after the last IMP doses of induction Phase).

Observation

no further treatment; tumour assessment, follow-up documentation and collection of biological material will be done according to the same schedule as Arm 1.

Group Type: NO_INTERVENTION

No interventions assigned to this group

Interventions

Ipilimumab

Induction phase: i.v. 3 mg/kg, once every 3 weeks × 4 cycles, to start within 6-8 weeks (42-56 days) from start of chemotherapy cycle 4, and not more than 2 weeks (14 days) after the date of randomisation)

Intervention Type: DRUG

Nivolumab

Induction phase: Nivolumab i.v. 1 mg/kg, once every 3 weeks × 4 cycles, to start within 6-8 weeks (42-56 days) from start of chemotherapy cycle 4, and not more than 2 weeks (14 days) after the date of randomisation) Maintenance Phase: Nivolumab 240 mg i.v once every 2 weeks for a maximum of 12 months from start of maintenance (the first dose of maintenance nivolumab will be administered 3 weeks after the last IMP doses of induction Phase).

Intervention Type: DRUG

Other Intervention Names

Yervoy; Opdivo

Eligibility Criteria

Inclusion Criteria

• Histologically or cytologically confirmed small cell lung carcinoma.
• Untreated limited-stage disease (with the exception of one cycle of chemotherapy given prior to enrolment) as defined by stage I-IIIB based on 7th TNM classification (IASLC classification for SCLC proposal). M0 proven by whole body FDG-PET CT including a contrast-enhanced CT of thorax and upper abdomen (incl. liver, kidney, adrenals); OR contrast-enhanced CT of thorax and upper abdomen (incl. liver, kidney, adrenals) and bone scan; AND brain MRI (or contrast enhanced CT of the brain) within 28 days before start of chemotherapy.
• Age ≥ 18 years.
• ECOG performance status 0-1.
• Adequate haematological function: haemoglobin > 9 g/dL, neutrophils count >1.5×109/L, platelet count > 100 × 109/L.
• Adequate liver function: total bilirubin < 2.5 × ULN, ALT and/or AST < 2.5 × ULN, alkaline phosphatase < 5 ULN.
• Adequate renal function: Calculated creatinine clearance ≥ 30 mL/min (Cockroft-Gault).
• Pulmonary function FEV1 of 1.0L or > 40% predicted value and DLCO > 40% predicted value.
• Patient capable of proper therapeutic compliance, and accessible for correct follow-up.
• Women of childbearing potential, including women who had their last menstrual period in the last 2 years, must have a negative serum or urine pregnancy test within 7 days before beginning of chemotherapy.
• All sexually active men and women of childbearing potential must use an effective contraceptive method (two barrier methods or a barrier method plus a hormonal method) during the study treatment and for a period of at least 12 months following the last administration of trial drugs.
• Measurable or evaluable disease (according to RECIST 1.1 criteria). Not eligible: patients with only one measurable or evaluable tumour lesion which was resected or irradiated prior to enrolment.
• Written Informed Consent (IC) must be signed and dated by the patient and the investigator prior to any trial-related intervention for a) Chemo-radiotherapy treatment and PCI, and subsequent randomisation, including mandatory biological samples b) Optional biological material collection, long-term storage and future use of biological material for translational research.

• Chemo-radiotherapy completed per protocol: 4 cycles of chemotherapy, ≥85% of PTV of thoracic radiotherapy, as well as completed, mandatory PCI.
• Non-PD after chemo-radiotherapy and PCI.
• ECOG performance status 0-2.
• Recovery of all adverse events to a grade ≤1, except for fatigue, appetite, oesophagitis and renal impairment (where ≤2 is allowed) and alopecia (any grade).
• Women of childbearing potential, including women who had their last menstrual period in the last 2 years, must have a negative serum or urine pregnancy test within 7 days before randomisation.

Exclusion Criteria

• Patient with mixed small-cell and non-small-cell histologic features.
• Patient with pleural or pericardial effusions proven to be malignant.
• Patients who have had in the past 5 years any previous or concomitant malignancy EXCEPT adequately treated basal or squamous cell carcinoma of the skin, in situ carcinoma of the cervix or bladder, in situ ductal carcinoma of the breast (if no RT was involved).
• Patients with other serious diseases or clinical conditions, including but not limited to uncontrolled active infection and any other serious underlying medical processes that could affect the patient's capacity to participate in the study.
• Ongoing clinically serious infections requiring systemic antibiotic or antiviral, antimicrobial, antifungal therapy.
• Known or suspected hypersensitivity to nivolumab or ipilimumab or any of their excipients.
• Substance abuse, medical, psychological or social conditions that may interfere with the patient's participation in the study or evaluation of the study results.
• Documented history of severe autoimmune or immune mediated symptomatic disease that required prolonged (more than 2 months) systemic immunosuppressive (e.g. steroids) treatment, such as but not limited to ulcerative colitis and Crohn´s disease, rheumatoid arthritis, systemic progressive sclerosis (scleroderma), systemic lupus erythematosus, or autoimmune vasculitis (eg, Wegener's granulomatosis).
• Subjects with an autoimmune paraneoplastic syndrome requiring concurrent immunosuppressive treatment.
• Interstitial lung disease or pulmonary fibrosis.
• Women who are pregnant or in the period of lactation.
• Sexually active men and women of childbearing potential who are not willing to use an effective contraceptive method during the study.
• Patients with any concurrent anticancer systemic therapy (except for chemotherapy cycle 1).
• HIV, active Hepatitis B or Hepatitis C infection.
• Previous radiotherapy to the thorax (prior to inclusion), including RT for breast cancer.
• Planned radiotherapy to lung of mean dose > 20 Gy or V20 > 35 %.
• Patients who received treatment with an investigational drug agent during the 3 weeks before enrolment in the study.
• Prior chemotherapy or radiotherapy for SCLC. Exception: one cycle of chemotherapy (as specified to section 10.2 of the protocol) may be administered prior to enrolment.

• Less than 4 cycles of chemotherapy administered, less than 85% PTV of thoracic radiotherapy delivered, or PCI not completed.
• Progressive disease after chemo-radiotherapy and PCI.

• Minimum Eligible Age: 18 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Intergroupe Francophone de Cancerologie Thoracique

OTHER

Sponsor Role: collaborator

Ludwig Center for Cancer Research of Lausanne

OTHER

Sponsor Role: collaborator

Frontier Science Foundation, Hellas

OTHER

Sponsor Role: collaborator

Bristol-Myers Squibb

INDUSTRY

Sponsor Role: collaborator

ETOP IBCSG Partners Foundation

NETWORK

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Solange Peters, MD PhD

Role: STUDY_CHAIR

European Thoracic Oncology Platform (ETOP)

Dirk De Ruysscher, MD PhD

Role: STUDY_CHAIR

Maastro Clinic, Maastricht, The Netherlands

Locations

Bendigo Hospital

Bendigo, , Australia

Coffs Harbour Health Campus

Coffs Harbour, , Australia

Royal Brisbane and Women's Hospital (QLD)

Herston, , Australia

Royal Hobart Hospital

Hobart, , Australia

NNSWLHD - The Tweed Hospital

Lismore, , Australia

Austin Hospital

Melbourne, , Australia

Riverina Cancer Centre

Mount Kuring-Gai, , Australia

Port Macquarie Base Hospital

Port Macquarie, , Australia

Epworth HealthCare - Richmond

Richmond, , Australia

Princess Alexandra Hospital

Woolloongabba, , Australia

University Hospital Gasthuisberg, KU Leuven

Leuven, , Belgium

Avignon - Institut Sainte-Catherine

Avignon, , France

Caen - Centre François Baclesse

Caen, , France

CHU

Caen, , France

Percy/Armées

Clamart, , France

Clermont-Ferrand

Clermont-Ferrand, , France

Créteil - CHI

Créteil, , France

CHU

Grenoble, , France

Centre Hospitalier Général

Le Mans, , France

Hôpital Louis Pradel

Lyon, , France

Lyon - Sud

Lyon, , France

AP-HM

Marseille, , France

Centre Hospitalier Universitaire de Montpellier

Montpellier, , France

CH

Mulhouse, , France

CRLCC

Nantes, , France

Nice - CRLCC

Nice, , France

Orléans - CH

Orléans, , France

Paris - Bichat

Paris, , France

Paris - Saint-Louis

Paris, , France

Paris - Tenon

Paris, , France

CHU

Rennes, , France

Nouvel Hôpital Civil

Strasbourg, , France

Suresnes

Suresnes, , France

CHI

Toulon, , France

CHU

Toulouse, , France

CHU

Tours, , France

Institut Gustave Roussy

Villejuif, , France

Klinikum Esslingen

Esslingen am Neckar, , Germany

LungenClinic Grosshansdorf GmbH

Großhansdorf, , Germany

Klinikum München-Bogenhausen

München, , Germany

Thoracic Oncology Centre Munich

München, , Germany

Pius-Hospital Oldenburg

Oldenburg, , Germany

Krankenhaus der Barmherzigen Brüder

Trier, , Germany

Universitätsklinikum Tübingen

Tübingen, , Germany

VUMC

Amsterdam, , Netherlands

Maastro Clinic

Maastricht, , Netherlands

Hospital General Universitario Alicante

Alicante, , Spain

Hospital Universitario Cruces

Barakaldo, , Spain

Hospital De La Santa Creu I Sant Pau

Barcelona, , Spain

Clinico San Carlos

Madrid, , Spain

Hospital Puerta de Hierro

Madrid, , Spain

Hospital Universitario 12 Octubre

Madrid, , Spain

Hospital Universitario Fundacion Jimenez Díaz

Madrid, , Spain

Hospital Universitario Central De Asturias

Oviedo, , Spain

Hospital Virgen De La Salud

Toledo, , Spain

Hospital Clínico Universitario De Valencia

Valencia, , Spain

Centre Hospitalier Universitaire Vaudois

Lausanne, , Switzerland

University Hospital Zürich

Zurich, , Switzerland

St James' University Hospital

Leeds, , United Kingdom

Royal Marsden

London, , United Kingdom

The Christie NHS Foundation Trust

Manchester, , United Kingdom

Countries

Australia; Belgium; France; Germany; Netherlands; Spain; Switzerland; United Kingdom

References

Lynch TJ, Bondarenko I, Luft A, Serwatowski P, Barlesi F, Chacko R, Sebastian M, Neal J, Lu H, Cuillerot JM, Reck M. Ipilimumab in combination with paclitaxel and carboplatin as first-line treatment in stage IIIB/IV non-small-cell lung cancer: results from a randomized, double-blind, multicenter phase II study. J Clin Oncol. 2012 Jun 10;30(17):2046-54. doi: 10.1200/JCO.2011.38.4032. Epub 2012 Apr 30.

Reference Type: BACKGROUND

PMID: 22547592 (View on PubMed)

Reck M, Bondarenko I, Luft A, Serwatowski P, Barlesi F, Chacko R, Sebastian M, Lu H, Cuillerot JM, Lynch TJ. Ipilimumab in combination with paclitaxel and carboplatin as first-line therapy in extensive-disease-small-cell lung cancer: results from a randomized, double-blind, multicenter phase 2 trial. Ann Oncol. 2013 Jan;24(1):75-83. doi: 10.1093/annonc/mds213. Epub 2012 Aug 2.

Reference Type: BACKGROUND

PMID: 22858559 (View on PubMed)

Margolin K, Ernstoff MS, Hamid O, Lawrence D, McDermott D, Puzanov I, Wolchok JD, Clark JI, Sznol M, Logan TF, Richards J, Michener T, Balogh A, Heller KN, Hodi FS. Ipilimumab in patients with melanoma and brain metastases: an open-label, phase 2 trial. Lancet Oncol. 2012 May;13(5):459-65. doi: 10.1016/S1470-2045(12)70090-6. Epub 2012 Mar 27.

Reference Type: BACKGROUND

PMID: 22456429 (View on PubMed)

Provided Documents

Document Type: Study Protocol

View Document

Document Type: Statistical Analysis Plan

View Document

Related Links

http://www.etop-eu.org/

Sponsor

Other Identifiers

2013-002609-78

Identifier Type: EUDRACT_NUMBER

Identifier Source: secondary_id

CA184-310

Identifier Type: OTHER

Identifier Source: secondary_id

SNCTP000000166

Identifier Type: REGISTRY

Identifier Source: secondary_id

ETOP/IFCT 4-12

Identifier Type: -

Identifier Source: org_study_id