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

NCT02046733 | Completed Phase 2 Results DMC

• 4 other identifiers: ETOP/IFCT 4-122013-002609-78CA184-310SNCTP000000166
• Study Type: interventional
• Target: 222
• Locations: 8 countries
• Sites: 61

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.

Conditions

Limited Stage Small Cell Lung Cancer; Small Cell Lung Cancer

Keywords

SCLC; CTLA-4

Outcome Measures

Primary Outcomes (1)

• 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 Outcomes (4)

• Overall Survival (OS)

  From the date of randomization until death from any cause, up to 5.5 years.

• Objective Response (OR)

  From randomisation to termination of trial treatment, for a maximum of 12 months from start of maintenance phase.

• Time-to-treatment Failure (TTF)

  From the date of randomization to treatment failure for any reason, up to 4.5 years.

• Adverse Events

  Adverse events were assessed from randomization to 100 days after the last dose of study treatment, up to 4.5 years.

Study Arms (2)

Nivolumab + Ipilimumab

EXPERIMENTAL

\- 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; Drug: Nivolumab

Observation

NO INTERVENTION

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

Interventions

Ipilimumab 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)

Also known as: Yervoy

Nivolumab + Ipilimumab

Nivolumab 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).

Also known as: Opdivo

Nivolumab + Ipilimumab

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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.

You may not qualify if:

• 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.
• Planned radiotherapy to lung of mean dose \> 20 Gy or V20 \> 35 %.

Sponsors & Collaborators

• ETOP IBCSG Partners Foundation: lead
• Intergroupe Francophone de Cancerologie Thoracique: collaborator
• Ludwig Center for Cancer Research of Lausanne: collaborator
• Frontier Science Foundation, Hellas: collaborator
• Bristol-Myers Squibb: collaborator

Study Sites (61)

Bendigo Hospital

Bendigo, Australia

Location

Coffs Harbour Health Campus

Coffs Harbour, Australia

Location

Royal Brisbane and Women's Hospital (QLD)

Herston, Australia

Location

Royal Hobart Hospital

Hobart, Australia

Location

NNSWLHD - The Tweed Hospital

Lismore, Australia

Location

Austin Hospital

Melbourne, Australia

Location

Riverina Cancer Centre

Mount Kuring-Gai, Australia

Location

Port Macquarie Base Hospital

Port Macquarie, Australia

Location

Epworth HealthCare - Richmond

Richmond, Australia

Location

Princess Alexandra Hospital

Woolloongabba, Australia

Location

University Hospital Gasthuisberg, KU Leuven

Leuven, 3000, Belgium

Location

Avignon - Institut Sainte-Catherine

Avignon, France

Location

Caen - Centre François Baclesse

Caen, France

Location

CHU

Caen, France

Location

Percy/Armées

Clamart, France

Location

Clermont-Ferrand

Clermont-Ferrand, France

Location

Créteil - CHI

Créteil, France

Location

CHU

Grenoble, France

Location

Centre Hospitalier Général

Le Mans, 72037, France

Location

Hôpital Louis Pradel

Lyon, France

Location

Lyon - Sud

Lyon, France

Location

AP-HM

Marseille, France

Location

Centre Hospitalier Universitaire de Montpellier

Montpellier, France

Location

CH

Mulhouse, France

Location

CRLCC

Nantes, France

Location

Nice - CRLCC

Nice, France

Location

Orléans - CH

Orléans, France

Location

Paris - Bichat

Paris, France

Location

Paris - Saint-Louis

Paris, France

Location

Paris - Tenon

Paris, France

Location

CHU

Rennes, France

Location

Nouvel Hôpital Civil

Strasbourg, France

Location

Suresnes

Suresnes, France

Location

CHI

Toulon, France

Location

CHU

Toulouse, France

Location

CHU

Tours, France

Location

Institut Gustave Roussy

Villejuif, France

Location

Klinikum Esslingen

Esslingen am Neckar, Germany

Location

LungenClinic Grosshansdorf GmbH

Großhansdorf, 22927, Germany

Location

Klinikum München-Bogenhausen

München, Germany

Location

Thoracic Oncology Centre Munich

München, Germany

Location

Pius-Hospital Oldenburg

Oldenburg, Germany

Location

Krankenhaus der Barmherzigen Brüder

Trier, Germany

Location

Universitätsklinikum Tübingen

Tübingen, Germany

Location

VUMC

Amsterdam, Netherlands

Location

Maastro Clinic

Maastricht, Netherlands

Location

Hospital General Universitario Alicante

Alicante, Spain

Location

Hospital Universitario Cruces

Barakaldo, Spain

Location

Hospital De La Santa Creu I Sant Pau

Barcelona, Spain

Location

Clinico San Carlos

Madrid, Spain

Location

Hospital Puerta de Hierro

Madrid, Spain

Location

Hospital Universitario 12 Octubre

Madrid, Spain

Location

Hospital Universitario Fundacion Jimenez Díaz

Madrid, Spain

Location

Hospital Universitario Central De Asturias

Oviedo, Spain

Location

Hospital Virgen De La Salud

Toledo, Spain

Location

Hospital Clínico Universitario De Valencia

Valencia, Spain

Location

Centre Hospitalier Universitaire Vaudois

Lausanne, Switzerland

Location

University Hospital Zürich

Zurich, Switzerland

Location

St James' University Hospital

Leeds, United Kingdom

Location

Royal Marsden

London, United Kingdom

Location

The Christie NHS Foundation Trust

Manchester, United Kingdom

Location

Related Publications (3)

• 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.

  PMID: 22547592 BACKGROUND

• 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.

  PMID: 22858559 BACKGROUND

• 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.

  PMID: 22456429 BACKGROUND

Related Links

• Sponsor

MeSH Terms

Conditions

Small Cell Lung Carcinoma; Diabetes Mellitus, Insulin-Dependent, 12

Interventions

Ipilimumab; Nivolumab

Condition Hierarchy (Ancestors)

Carcinoma, Bronchogenic; Bronchial Neoplasms; Lung Neoplasms; Respiratory Tract Neoplasms; Thoracic Neoplasms; Neoplasms by Site; Neoplasms; Lung Diseases; Respiratory Tract Diseases

Intervention Hierarchy (Ancestors)

Antibodies, Monoclonal, Humanized; Antibodies, Monoclonal; Antibodies; Immunoglobulins; Immunoproteins; Blood Proteins; Proteins; Amino Acids, Peptides, and Proteins; Serum Globulins; Globulins

Limitations and Caveats

Because of the low accrual rate, as well as additional internal strategic considerations unrelated to the scientific rational or trial design, Bristol-Myers Squibb (BMS) decided not to continue funding the STIMULI trial. Thus, the trial Steering Committee decided to close the accrual permanently as of April 30, 2019. The statistical design was modified and the primary endpoint of the trial was finally defined as only the PFS (previous: co-primary PFS and OS).

Results Point of Contact

• Title: Heidi Roschitzki-Voser
• Organization: European Thoracic Oncology Platform (ETOP)

STIMULI@etop-eu.org

+41 31 511 94 18

Study Officials

• Solange Peters, MD PhD

  European Thoracic Oncology Platform (ETOP)

  STUDY CHAIR

• Dirk De Ruysscher, MD PhD

  Maastro Clinic, Maastricht, The Netherlands

  STUDY CHAIR

Publication Agreements

• PI is Sponsor Employee: No
• Restrictive Agreement: No

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: NETWORK
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: January 17, 2014
• First Posted: January 28, 2014
• Study Start: December 18, 2015
• Primary Completion: May 25, 2020
• Study Completion: February 1, 2022
• Last Updated: November 8, 2024
• Results First Posted: November 8, 2024

Record last verified: 2024-09

Data Sharing

• IPD Sharing: Will not share

Locations

FR (26); CH (2); ES (10); GB (3); AU (10); DE (7); BE (1); NL (2)