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

Small Cell Lung Cancer Clinical Trial

— STIMULI  

Official title:

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

Clinical Trial Details — Status: Active, not recruiting

Administrative data

• NCT number: NCT02046733
• Other study ID #: ETOP/IFCT 4-12
• Secondary ID: 2013-002609-78CA
• Status: Active, not recruiting
• Phase: Phase 2
• Start date: July 28, 2014
• Est. completion date: June 2022

Study information

• Verified date: February 2021
• Source: European Thoracic Oncology Platform
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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 information / eligibility

• Status: Active, not recruiting
• Enrollment: 174
• Est. completion date: June 2022
• Est. primary completion date: May 2020
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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

1. Chemo-radiotherapy treatment and PCI, and subsequent randomisation, including mandatory biological samples

2. Optional biological material collection, long-term storage and future use of biological material for translational research

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 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) may be administered prior to enrolment.

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

Related Conditions & MeSH terms

• Limited Stage Small Cell Lung Cancer
• Lung Neoplasms
• Small Cell Lung Cancer
• Small Cell Lung Carcinoma

Intervention

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)
• 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).

Locations

Country	Name	City	State
Australia	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
Belgium	University Hospital Gasthuisberg, KU Leuven	Leuven
France	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	Creteil
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
Germany	Klinikum Esslingen	Esslingen
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
Netherlands	VUMC	Amsterdam
Netherlands	Maastro Clinic	Maastricht
Spain	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
Switzerland	Centre Hospitalier Universitaire Vaudois	Lausanne
Switzerland	University Hospital Zürich	Zürich
United Kingdom	St James' University Hospital	Leeds
United Kingdom	Royal Marsden	London
United Kingdom	The Christie NHS Foundation Trust	Manchester

Sponsors (5)

Lead Sponsor	Collaborator
European Thoracic Oncology Platform	Bristol-Myers Squibb, Frontier Science Foundation, Hellas, Intergroupe Francophone de Cancerologie Thoracique, Ludwig Center for Cancer Research of Lausanne

Countries where clinical trial is conducted

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

References & 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. Erratum in: J Clin Oncol. 2012 Oct 10;30(29):3654. — View Citation

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. — View Citation

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. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Overall survival	Defined as time from the date of randomisation until death from any cause. Censoring will occur at the last follow-up date.	From date of randomisation until death from any cause, assessed up to a maximum of 6,5 years
Primary	Progression-free survival determined by RECIST 1.1	Defined as time from the date of randomisation until documented progression or death, if progression is not documented. Censoring will occur at the last tumor assessment only if patient is lost to follow-up.	From date of randomisation until documented progression or death, if progression is not documented, assessed up to a maximum of 6,5 years
Secondary	Objective response	Objective response is defined as best overall response (CR or PR) across all assessment time-points during the period from randomisation to termination of trial treatment.; Objective response to chemo-radiotherapy will be determined by tumour assessment around week 15.; Objective response to trial treatment will be determined using RECIST 1.1 criteria	From randomisation to termination of trial treatment, up to a maximum of 2 years
Secondary	Time to treatment failure	Defined as time from the date of randomisation to discontinuation of treatment for any reason (including progression of disease, treatment toxicity, refusal and death). Censoring will occur at the last follow-up date.	From date of randomisation until discontinuation of treatment for any reason, assessed up to a maximum of 6.5 years
Secondary	Adverse events	Toxicity of study treatment is assessed by adverse events classified according to NCI CTCAE version 4.	Up to a maximum of 6.5 years

External Links

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