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

Sponsor

ETOP IBCSG Partners Foundation (Other)

Overall Status

Active, not recruiting

CT.gov ID

NCT02046733

Collaborator

Intergroupe Francophone de Cancerologie Thoracique (Other), Ludwig Center for Cancer Research of Lausanne (Other), Frontier Science Foundation, Hellas (Other), Bristol-Myers Squibb (Industry)

174

Enrollment

Locations

Arms

94.1

Anticipated Duration (Months)

2.9

Patients Per Site

Patients Per Site Per Month

Study Details

Study Description

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.

Condition or Disease	Intervention/Treatment	Phase
Limited Stage Small Cell Lung Cancer Small Cell Lung Cancer	Drug: Ipilimumab Drug: Nivolumab	Phase 2

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 Design

Study Type:

Interventional

Actual Enrollment :

174 participants

Allocation:

Randomized

Intervention Model:

Parallel Assignment

Masking:

None (Open Label)

Primary Purpose:

Treatment

Official Title:

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

Actual Study Start Date :

Jul 28, 2014

Actual Primary Completion Date :

May 1, 2020

Anticipated Study Completion Date :

Jun 1, 2022

Arms and Interventions

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.

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.

Outcome Measures

Primary Outcome Measures

Overall survival [From date of randomisation until death from any cause, assessed up to a maximum of 6,5 years]
Defined as time from the date of randomisation until death from any cause. Censoring will occur at the last follow-up date.
Progression-free survival determined by RECIST 1.1 [From date of randomisation until documented progression or death, if progression is not documented, assessed up to a maximum of 6,5 years]
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.

Secondary Outcome Measures

Objective response [From randomisation to termination of trial treatment, up to a maximum of 2 years]
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
Time to treatment failure [From date of randomisation until discontinuation of treatment for any reason, assessed up to a maximum of 6.5 years]
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.
Adverse events [Up to a maximum of 6.5 years]
Toxicity of study treatment is assessed by adverse events classified according to NCI CTCAE version 4.

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

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

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

Contacts and Locations

Locations

	Site	City	Country	Postal Code
1	Bendigo Hospital	Bendigo	Australia
2	Coffs Harbour Health Campus	Coffs Harbour	Australia
3	Royal Brisbane and Women's Hospital (QLD)	Herston	Australia
4	Royal Hobart Hospital	Hobart	Australia
5	NNSWLHD - The Tweed Hospital	Lismore	Australia
6	Austin Hospital	Melbourne	Australia
7	Riverina Cancer Centre	Mount Kuring-gai	Australia
8	Port Macquarie Base Hospital	Port Macquarie	Australia
9	Epworth HealthCare - Richmond	Richmond	Australia
10	Princess Alexandra Hospital	Woolloongabba	Australia
11	University Hospital Gasthuisberg, KU Leuven	Leuven	Belgium	3000
12	Avignon - Institut Sainte-Catherine	Avignon	France
13	Caen - Centre François Baclesse	Caen	France
14	CHU	Caen	France
15	Percy/Armées	Clamart	France
16	Clermont-Ferrand	Clermont-Ferrand	France
17	Créteil - CHI	Creteil	France
18	CHU	Grenoble	France
19	Centre Hospitalier Général	Le Mans	France	72037
20	Hôpital Louis Pradel	Lyon	France
21	Lyon - Sud	Lyon	France
22	AP-HM	Marseille	France
23	Centre Hospitalier Universitaire de Montpellier	Montpellier	France
24	CH	Mulhouse	France
25	CRLCC	Nantes	France
26	Nice - CRLCC	Nice	France
27	Orléans - CH	Orléans	France
28	Paris - Bichat	Paris	France
29	Paris - Saint-Louis	Paris	France
30	Paris - Tenon	Paris	France
31	CHU	Rennes	France
32	Nouvel Hôpital Civil	Strasbourg	France
33	Suresnes	Suresnes	France
34	CHI	Toulon	France
35	CHU	Toulouse	France
36	CHU	Tours	France
37	Institut Gustave Roussy	Villejuif	France
38	Klinikum Esslingen	Esslingen	Germany
39	LungenClinic Grosshansdorf GmbH	Grosshansdorf	Germany	22927
40	Klinikum München-Bogenhausen	München	Germany
41	Thoracic Oncology Centre Munich	München	Germany
42	Pius-Hospital Oldenburg	Oldenburg	Germany
43	Krankenhaus der Barmherzigen Brüder	Trier	Germany
44	Universitätsklinikum Tübingen	Tübingen	Germany
45	VUMC	Amsterdam	Netherlands
46	Maastro Clinic	Maastricht	Netherlands
47	Hospital General Universitario Alicante	Alicante	Spain
48	Hospital Universitario Cruces	Barakaldo	Spain
49	Hospital De La Santa Creu I Sant Pau	Barcelona	Spain
50	Clinico San Carlos	Madrid	Spain
51	Hospital Puerta de Hierro	Madrid	Spain
52	Hospital Universitario 12 Octubre	Madrid	Spain
53	Hospital Universitario Fundacion Jimenez Díaz	Madrid	Spain
54	Hospital Universitario Central De Asturias	Oviedo	Spain
55	Hospital Virgen De La Salud	Toledo	Spain
56	Hospital Clínico Universitario De Valencia	Valencia	Spain
57	Centre Hospitalier Universitaire Vaudois	Lausanne	Switzerland
58	University Hospital Zürich	Zürich	Switzerland
59	St James' University Hospital	Leeds	United Kingdom
60	Royal Marsden	London	United Kingdom
61	The Christie NHS Foundation Trust	Manchester	United Kingdom

Sponsors and Collaborators

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

Investigators

Study Chair: Solange Peters, MD PhD, European Thoracic Oncology Platform (ETOP)
Study Chair: Dirk De Ruysscher, MD PhD, Maastro Clinic, Maastricht, The Netherlands