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Trial details imported from ClinicalTrials.gov

For full trial details, please see the original record at https://clinicaltrials.gov/show/NCT02046733




Registration number
NCT02046733
Ethics application status
Date submitted
17/01/2014
Date registered
28/01/2014
Date last updated
1/07/2019

Titles & IDs
Public title
Small Cell Lung Carcinoma Trial With Nivolumab and IpiliMUmab in LImited Disease
Scientific title
A Randomised Open-label Phase II Trial of Consolidation With Nivolumab and Ipilimumab in Limited-stage SCLC After Chemo-radiotherapy
Secondary ID [1] 0 0
2013-002609-78
Secondary ID [2] 0 0
ETOP/IFCT 4-12
Universal Trial Number (UTN)
Trial acronym
STIMULI
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Limited Stage Small Cell Lung Cancer 0 0
Small Cell Lung Cancer 0 0
Condition category
Condition code
Cancer 0 0 0 0
Lung - Mesothelioma
Cancer 0 0 0 0
Lung - Non small cell
Cancer 0 0 0 0
Lung - Small cell

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Treatment: Drugs - Ipilimumab
Treatment: Drugs - Nivolumab

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

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.


Treatment: Drugs: 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)

Treatment: Drugs: 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 code [1] 0 0
Treatment: Drugs
Comparator / control treatment
Control group

Outcomes
Primary outcome [1] 0 0
Overall survival - Defined as time from the date of randomisation until death from any cause. Censoring will occur at the last follow-up date.
Timepoint [1] 0 0
From date of randomisation until death from any cause, assessed up to a maximum of 6,5 years
Primary outcome [2] 0 0
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.
Timepoint [2] 0 0
From date of randomisation until documented progression or death, if progression is not documented, assessed up to a maximum of 6,5 years
Secondary outcome [1] 0 0
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
Timepoint [1] 0 0
From randomisation to termination of trial treatment, up to a maximum of 2 years
Secondary outcome [2] 0 0
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.
Timepoint [2] 0 0
From date of randomisation until discontinuation of treatment for any reason, assessed up to a maximum of 6.5 years
Secondary outcome [3] 0 0
Toxicity - Adverse events classified according to NCI CTCAE version 4.
Timepoint [3] 0 0
Up to a maximum of 6.5 years

Eligibility
Key inclusion criteria
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.
Minimum age
18 Years
Maximum age
No limit
Gender
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
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

Study design
Purpose of the study
Treatment
Allocation to intervention
Randomised controlled trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Masking / blinding
Open (masking not used)
Who is / are masked / blinded?



Intervention assignment
Parallel
Other design features
Phase
Phase 2
Type of endpoint(s)
Statistical methods / analysis

Recruitment
Recruitment status
Active, not recruiting
Data analysis
Reason for early stopping/withdrawal
Other reasons
Date of first participant enrolment
Anticipated
Actual
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
Actual
Sample size
Target
Accrual to date
Final
Recruitment in Australia
Recruitment state(s)
Recruitment hospital [1] 0 0
Bendigo Hospital - Bendigo
Recruitment hospital [2] 0 0
Coffs Harbour Health Campus - Coffs Harbour
Recruitment hospital [3] 0 0
Royal Brisbane and Women's Hospital (QLD) - Herston
Recruitment hospital [4] 0 0
Royal Hobart Hospital - Hobart
Recruitment hospital [5] 0 0
NNSWLHD - The Tweed Hospital - Lismore
Recruitment hospital [6] 0 0
Austin Hospital - Melbourne
Recruitment hospital [7] 0 0
Riverina Cancer Centre - Mount Kuring-gai
Recruitment hospital [8] 0 0
Port Macquarie Base Hospital - Port Macquarie
Recruitment hospital [9] 0 0
Epworth HealthCare - Richmond - Richmond
Recruitment hospital [10] 0 0
Princess Alexandra Hospital - Woolloongabba
Recruitment postcode(s) [1] 0 0
- Bendigo
Recruitment postcode(s) [2] 0 0
- Coffs Harbour
Recruitment postcode(s) [3] 0 0
- Herston
Recruitment postcode(s) [4] 0 0
- Hobart
Recruitment postcode(s) [5] 0 0
- Lismore
Recruitment postcode(s) [6] 0 0
- Melbourne
Recruitment postcode(s) [7] 0 0
- Mount Kuring-gai
Recruitment postcode(s) [8] 0 0
- Port Macquarie
Recruitment postcode(s) [9] 0 0
- Richmond
Recruitment postcode(s) [10] 0 0
- Woolloongabba
Recruitment outside Australia
Country [1] 0 0
Belgium
State/province [1] 0 0
Leuven
Country [2] 0 0
France
State/province [2] 0 0
Avignon
Country [3] 0 0
France
State/province [3] 0 0
Caen
Country [4] 0 0
France
State/province [4] 0 0
Clamart
Country [5] 0 0
France
State/province [5] 0 0
Clermont-Ferrand
Country [6] 0 0
France
State/province [6] 0 0
Creteil
Country [7] 0 0
France
State/province [7] 0 0
Grenoble
Country [8] 0 0
France
State/province [8] 0 0
Le Mans
Country [9] 0 0
France
State/province [9] 0 0
Lyon
Country [10] 0 0
France
State/province [10] 0 0
Marseille
Country [11] 0 0
France
State/province [11] 0 0
Montpellier
Country [12] 0 0
France
State/province [12] 0 0
Mulhouse
Country [13] 0 0
France
State/province [13] 0 0
Nantes
Country [14] 0 0
France
State/province [14] 0 0
Nice
Country [15] 0 0
France
State/province [15] 0 0
Orléans
Country [16] 0 0
France
State/province [16] 0 0
Paris
Country [17] 0 0
France
State/province [17] 0 0
Rennes
Country [18] 0 0
France
State/province [18] 0 0
Strasbourg
Country [19] 0 0
France
State/province [19] 0 0
Suresnes
Country [20] 0 0
France
State/province [20] 0 0
Toulon
Country [21] 0 0
France
State/province [21] 0 0
Toulouse
Country [22] 0 0
France
State/province [22] 0 0
Tours
Country [23] 0 0
France
State/province [23] 0 0
Villejuif
Country [24] 0 0
Germany
State/province [24] 0 0
Esslingen
Country [25] 0 0
Germany
State/province [25] 0 0
Grosshansdorf
Country [26] 0 0
Germany
State/province [26] 0 0
München
Country [27] 0 0
Germany
State/province [27] 0 0
Oldenburg
Country [28] 0 0
Germany
State/province [28] 0 0
Trier
Country [29] 0 0
Germany
State/province [29] 0 0
Tübingen
Country [30] 0 0
Netherlands
State/province [30] 0 0
Amsterdam
Country [31] 0 0
Netherlands
State/province [31] 0 0
Maastricht
Country [32] 0 0
Spain
State/province [32] 0 0
Alicante
Country [33] 0 0
Spain
State/province [33] 0 0
Barakaldo
Country [34] 0 0
Spain
State/province [34] 0 0
Barcelona
Country [35] 0 0
Spain
State/province [35] 0 0
Madrid
Country [36] 0 0
Spain
State/province [36] 0 0
Oviedo
Country [37] 0 0
Spain
State/province [37] 0 0
Toledo
Country [38] 0 0
Spain
State/province [38] 0 0
Valencia
Country [39] 0 0
Switzerland
State/province [39] 0 0
Lausanne
Country [40] 0 0
Switzerland
State/province [40] 0 0
Zürich
Country [41] 0 0
United Kingdom
State/province [41] 0 0
Leeds
Country [42] 0 0
United Kingdom
State/province [42] 0 0
London
Country [43] 0 0
United Kingdom
State/province [43] 0 0
Manchester

Funding & Sponsors
Primary sponsor type
Other
Name
European Thoracic Oncology Platform
Address
Country
Other collaborator category [1] 0 0
Other
Name [1] 0 0
Intergroupe Francophone de Cancerologie Thoracique
Address [1] 0 0
Country [1] 0 0
Other collaborator category [2] 0 0
Other
Name [2] 0 0
Ludwig Center for Cancer Research of Lausanne
Address [2] 0 0
Country [2] 0 0
Other collaborator category [3] 0 0
Other
Name [3] 0 0
Frontier Science Foundation, Hellas
Address [3] 0 0
Country [3] 0 0
Other collaborator category [4] 0 0
Commercial sector/Industry
Name [4] 0 0
Bristol-Myers Squibb
Address [4] 0 0
Country [4] 0 0

Ethics approval
Ethics application status

Summary
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.
Trial website
https://clinicaltrials.gov/show/NCT02046733
Trial related presentations / 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.
Public notes

Contacts
Principal investigator
Name 0 0
Solange Peters, MD PhD
Address 0 0
European Thoracic Oncology Platform (ETOP)
Country 0 0
Phone 0 0
Fax 0 0
Email 0 0
Contact person for public queries
Name 0 0
Address 0 0
Country 0 0
Phone 0 0
Fax 0 0
Email 0 0
Contact person for scientific queries

Summary results
Other publications