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

A Randomised Open-label Phase II Trial of Consolidation With Nivolumab and Ipilimumab in Limited-stage SCLC After Chemo-radiotherapy

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.

Study Overview

• Status: Completed
• Conditions: Small Cell Lung Cancer; Limited Stage Small Cell Lung Cancer
• Intervention / Treatment: Drug: Ipilimumab; Drug: Nivolumab

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).

• Study Type: Interventional
• Enrollment (Actual): 222
• Phase: Phase 2

Contacts and Locations

Study Locations

• Australia
  • Bendigo, Australia
    • Bendigo Hospital
  • Coffs Harbour, Australia
    • Coffs Harbour Health Campus
  • Herston, Australia
    • Royal Brisbane and Women's Hospital (QLD)
  • Hobart, Australia
    • Royal Hobart Hospital
  • Lismore, Australia
    • NNSWLHD - The Tweed Hospital
  • Melbourne, Australia
    • Austin Hospital
  • Mount Kuring-gai, Australia
    • Riverina Cancer Centre
  • Port Macquarie, Australia
    • Port Macquarie Base Hospital
  • Richmond, Australia
    • Epworth HealthCare - Richmond
  • Woolloongabba, Australia
    • Princess Alexandra Hospital
• Belgium
  • Leuven, Belgium, 3000
    • University Hospital Gasthuisberg, KU Leuven
• France
  • Avignon, France
    • Avignon - Institut Sainte-Catherine
  • Caen, France
    • CHU
  • Caen, France
    • Caen - Centre François Baclesse
  • Clamart, France
    • Percy/Armées
  • Clermont-Ferrand, France
    • Clermont-Ferrand
  • Creteil, France
    • Créteil - CHI
  • Grenoble, France
    • CHU
  • Le Mans, France, 72037
    • Centre Hospitalier Général
  • Lyon, France
    • Hôpital Louis Pradel
  • Lyon, France
    • Lyon - Sud
  • Marseille, France
    • AP-HM
  • Montpellier, France
    • Centre Hospitalier Universitaire de Montpellier
  • Mulhouse, France
    • CH
  • Nantes, France
    • CRLCC
  • Nice, France
    • Nice - CRLCC
  • Orléans, France
    • Orléans - CH
  • Paris, France
    • Paris - Saint-Louis
  • Paris, France
    • Paris - Tenon
  • Paris, France
    • Paris - Bichat
  • Rennes, France
    • CHU
  • Strasbourg, France
    • Nouvel Hôpital Civil
  • Suresnes, France
    • Suresnes
  • Toulon, France
    • CHI
  • Toulouse, France
    • CHU
  • Tours, France
    • CHU
  • Villejuif, France
    • Institut Gustave Roussy
• Germany
  • Esslingen, Germany
    • Klinikum Esslingen
  • Grosshansdorf, Germany, 22927
    • LungenClinic Grosshansdorf GmbH
  • München, Germany
    • Klinikum München-Bogenhausen
  • München, Germany
    • Thoracic Oncology Centre Munich
  • Oldenburg, Germany
    • Pius-Hospital Oldenburg
  • Trier, Germany
    • Krankenhaus der Barmherzigen Brüder
  • Tübingen, Germany
    • Universitätsklinikum Tübingen
• Netherlands
  • Amsterdam, Netherlands
    • VUMC
  • Maastricht, Netherlands
    • Maastro Clinic
• Spain
  • Alicante, Spain
    • Hospital General Universitario Alicante
  • Barakaldo, Spain
    • Hospital Universitario Cruces
  • Barcelona, Spain
    • Hospital de la Santa Creu i Sant Pau
  • Madrid, Spain
    • Hospital Puerta de Hierro
  • Madrid, Spain
    • Hospital Universitario Fundacion Jimenez Diaz
  • Madrid, Spain
    • Clinico San Carlos
  • Madrid, Spain
    • Hospital Universitario 12 Octubre
  • Oviedo, Spain
    • Hospital Universitario Central de Asturias
  • Toledo, Spain
    • Hospital Virgen de la Salud
  • Valencia, Spain
    • Hospital Clinico Universitario de Valencia
• Switzerland
  • Lausanne, Switzerland
    • Centre Hospitalier Universitaire Vaudois
  • Zürich, Switzerland
    • University Hospital Zurich
• United Kingdom
  • Leeds, United Kingdom
    • St James' University Hospital
  • London, United Kingdom
    • Royal Marsden
  • Manchester, United Kingdom
    • The Christie NHS Foundation Trust

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria for enrolment:

• 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.

Exclusion Criteria for enrolment:

• 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.

Inclusion Criteria for randomisation:

• 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 for randomisation:

• 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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: 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	Drug: 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); Other Names: Yervoy; 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).; Other Names: Opdivo
No Intervention: 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.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Progression-free Survival (PFS)	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.	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.

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Overall Survival (OS)	Defined as the time from the date of randomisation until death from any cause. Censoring for OS occurs at the last follow-up date.	From the date of randomization until death from any cause, up to 5.5 years.
Objective Response (OR)	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.	From randomisation to termination of trial treatment, for a maximum of 12 months from start of maintenance phase.
Time-to-treatment Failure (TTF)	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.	From the date of randomization to treatment failure for any reason, up to 4.5 years.
Adverse Events	Adverse events graded according to NCI CTCAE V4.0.	Adverse events were assessed from randomization to 100 days after the last dose of study treatment, up to 4.5 years.

Collaborators and Investigators

• Sponsor: ETOP IBCSG Partners Foundation
• Collaborators: Bristol-Myers Squibb; Intergroupe Francophone de Cancerologie Thoracique; Frontier Science Foundation, Hellas; Ludwig Center for Cancer Research of Lausanne
• Investigators: Study Chair: Solange Peters, MD PhD, European Thoracic Oncology Platform (ETOP); Study Chair: Dirk De Ruysscher, MD PhD, Maastro Clinic, Maastricht, The Netherlands

Publications and helpful links

General Publications

• 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. Erratum In: J Clin Oncol. 2012 Oct 10;30(29):3654.
• 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.
• 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.

Helpful Links

• Sponsor

Study record dates

Study Major Dates

• Study Start (Actual): December 18, 2015
• Primary Completion (Actual): May 25, 2020
• Study Completion (Actual): February 1, 2022

Study Registration Dates

• First Submitted: January 17, 2014
• First Submitted That Met QC Criteria: January 24, 2014
• First Posted (Estimated): January 28, 2014

Study Record Updates

• Last Update Posted (Actual): November 8, 2024
• Last Update Submitted That Met QC Criteria: September 2, 2024
• Last Verified: September 1, 2024

More Information

Terms related to this study

• Keywords: CTLA-4; SCLC
• Additional Relevant MeSH Terms: Neoplasms by Site; Neoplasms; Respiratory Tract Diseases; Lung Diseases; Respiratory Tract Neoplasms; Thoracic Neoplasms; Carcinoma, Bronchogenic; Bronchial Neoplasms; Lung Neoplasms; Small Cell Lung Carcinoma; Antineoplastic Agents, Immunological; Immune Checkpoint Inhibitors; Antineoplastic Agents; Molecular Mechanisms of Pharmacological Action; Nivolumab; Ipilimumab
• Other Study ID Numbers: ETOP/IFCT 4-12; 2013-002609-78 (EudraCT Number); CA184-310 (Other Identifier: Bristol-Myers Squibb); SNCTP000000166 (Registry Identifier: Swiss National Clinical Trials Portal (SNCTP))

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO