A randomised open-label phase II trial of consolidation with nivolumab and ipilimumab in limited-stage SCLC after chemo-radiotherapy

Lung cancer accounts for 12% of all incident cases of cancer, of which 13% are
small cell lung cancer (SCLC). Over 90% of SCLC patients are current or past
smokers. The median age at diagnosis exceeds 70 years and most patients have at
least one cardiovascular, respiratory, or metabolic co-morbidity. At the time
of diagnosis, 30% of patients with 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 (i.e. 50% of patients are still alive) of 16 to 24
months with current forms of treatment and only 15-25% long term survivors.

Because SCLC is a systemic disease, chemotherapy is and remains the backbone of
the treatment. Adequate local therapy, such as resection, chest radiography and
prophylactic cranial irradiation, nevertherless improves long-term survival
significantly when delivered together with systemic treatment. However, both
distant metastases and local recurrences remain problematic even after
concurrent chemo-radiotherapy and profylactic cranial irradiation. Many
targeted therapies have been evaluated in the treatment of SCLC, but, in
contrast to advanced-stage NSCLC (non-SCLC), none of these have been
successful.

Several studies in patients with NSCLC suggested an association of increased
immune cell infiltration into tumours with improved survival. In recent years,
a continuously improved identification of antigenic targets, the addition of
immunoadjuvants, and the production of more efficient delivery systems have
resulted in more efficient vaccines. These are able to elicit a potent immune
response, leading to the development of immunotherapy as a fundamentally new
treatment of NSCLC.

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 immune surveillance by expressing immune
checkpoint receptors. The goal of immune checkpoint inhibitor therapies is not
to activate the immune system to attack particular tar-gets on tumour cells,
but rather to remove inhibitory pathways that block effective anti-tumour 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. A combination treatment with
anti-CTLA-4 (e.g. ipilimumab) 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 plus ipilimumab will be administered as a consolidation treatment
after completion of a standard treatment including chemo-radiotherapy and
prophylactic cranial irradiation (PCI).

The primary objective is to evaluate if patients treated with
chemo-radiotherapy and prophylactic cranial irradiation followed by
consolidation treatment (nivolumab plus ipilimumab) have a better outcome in
terms of progression-free survival (time from date of randomisation until
documented progression of death, if progression is not documented) and overall
survival (time from date of randomisation until death from any cause), compared
to patients treated with chemo-radiotherapy and prophylactic cranial
irradiation without consolidation treatment.

Secondary objectives are:
* to evaluate secondary measures of clinical efficacy including objective
response rate (best overall response across all assessment time-points from
randomisation to termination of trial treatment) and time to treatment failure
(time from date of randomisation to discontinuation of treatment for any reason)
* to assess the safety and the tolerability of the treatment in both arms.

This is an open-label, randomised, two-arm, phase II international multi-centre
clinical trial with interim analysis for safety in patients with radically
treated limited-stage small cell lung carcinoma following completion of
thoracic radiotherapy concomitant to chemotherapy and prophylactic cranial
irradiation.

The trial consists of the following phases:
* Screening: baseline evaluations must be done within 28 days prior to enrolment
* Chemotherapy: will be started in the week following enrolment and consist of
4 cycles of cisplatin or carboplatin and etoposide, repeated every 3 weeks ;
Thoracic radiotherapy: twice-daily over 3 weeks or once-daily over 6 weeks,
with start on day 1 of the first or second chemotherapy cycle ; Prophylactic
cranial irradiation: start between day 8 and day 15 of cycle 4 of chemotherapy
and finished no later than day 29 from start of cycle 4.
* Randomisation: should take place 5-6 weeks after day 1 of cycle 4 of
chemotherapy. Only patients without disease progression can be randomised into
one of two treatment arms:
° Arm 1: Nivolumab + Ipilimumab consolidation, consisting of induction
phase (nivolumab + ipilimumab once every 3 weeks x 4 cycles - started 1-2 weeks
after randomisation) and maintenance phase (nivolumab once every 2 weeks for a
maximum of 12 weeks - first dose 3 weeks after last dose of induction phase)
° Arm 2: Observation (no further study treatment)
* End of treatment: Arm 1: within 30 days following the last administered dose
of trial treatment
Arm 2: within 30 days of tumour progression or
15 months after randomisation
Non-randomised subjects: within 30 days
following tumour progression or within 30 days following the last chemotherapy
cycle.
* Follow-up period: Before tumour progression: in first 18 months after
randomisation: together with CT scans, then every 12 (+/- 1) weeks until

tumour progression for a maximum of 4,5 years after the enrolment of the last
patient.
After tumour progression: every 12 weeks in the
1st year after randomisation starting from the date of progression,
then
every 6 months up to 4.5 years after enrolment of the last patient. This
applies to all patients
who
have been enrolled but not randomised.

After enrolment, the patient will receive standard of care treatment for
limited-stage small cell lung cancer, consisting of:
* Chemotherapy: will be started in the week following enrolment (alternatively,
maximum 1 cycle of chemotherapy may be administered before enrolment), and
consists of a total of 4 cycles of cisplatin (25 mg/m2 i.v. days 1 * 3 or 75
mg/ m2 on day 1) or carboplatin (AUC 5-6 i.v. on day 1), plus etoposide (100
mg/ m2 i.v. days 1 * 3), repeated every 3 weeks (+/- 3 days without cycle delay)
* Concomitant thoracic radiotherapy: accelerated twice-daily administration of
1.5 Gy × 30 over three weeks (preferred) or once-daily administration of 2 Gy
over six weeks. Two options are allowed: thoracic radiotherapy MUST start
either from day 1 of cycle 1 or day 1 of cycle 2. Start on day 1 of cycle 3 is
allowed if patient is enrolled after the first cycle only but should be
exceptional.
* Prophylactic cranial irradiation: 25 Gy in 10 fractions started between day 8
and day 15 of cycle 4 and finished no later then day 29 from start of cycle 4.

After randomisation (should take place 5-6 weeks after Day 1 of cycle 4):
* Arm 1 (Experimental arm):
° Induction phase: nivolumab (at a dose of 1 mg/kg) + ipililumab (at a
dose of 3mg/kg) every 3 weeks × 4 cycli, start 1-2 weeks after
randomisation
° Maintenance phase: nivolumab (240 mg) every 2 weeks for a maximum of 12
months from the start of the maintenance. The first dose will be
administered 3 weeks after the last
doses of the induction phase
* Arm 2 (Observational arm): Observation

Physical, radiological and lab examinations will be performed at the time of
study entry. In women who could become pregnant, a pregnancy test will be done
on blood serum or urine within 7 days prior to the start of the chemotherapy.
The test needs to be repeated within 7 days before randomisation, thereafter
each 6 weeks during the consolidation phase. A pregnancy test needs to be
repeated around 30 days and around 70 days after the end of the consolidation
phase. During the first phase of the study treatment (chemoradiotherapy) and
during the induction phase (first part of the consolidation phase), patients
will visit the study doctor every 3 weeks. During the maintenance phase (second
part of the consolidation phase) the patients will visit the study doctor every
2 weeks.
Also blood samples (1 teaspoon (5ml)) will be collected prior or during
enrolment in the study, at randomisation, at 9 weeks after randomisation, at 18
weeks after randomisation and at the time of tumour growth for the
determination of the serum concentration of biomarkers and circulating
antibodies. Additional, blood samples (0,5 - 10 teaspoons (2.5-50 ml)) for
future research will be requested to collect prior or during enrolment in the
study, at randomisation, at 9 weeks after randomisation and at 18 weeks after
randomisation.

Radiological examinations will be performed to determine the status of the
disease and the treatment effect. FDG-PET-CT may be performed at study entry,
which is not a routine assessment. The patient will have to be fasting for at
least 6 hours (drinking of water is allowed). Following injection of a
radioactive substance in a vein, the patient will have to wait for about one
hour. Then the scanning session will start and it may take up to 30 minutes. A
CT of thorax and upper abdomen will be performed at the end of the standard
treatment prior to randomisation and thereafter every 9 weeks (until 18
months), every 12 weeks (until year 2), every 6 months (year 3 and 4) and at
week 260 (at 5 years). The doctor may also suggest other tests, such as CT of
the brain, whole body PET-CT, bone scans and MRI (as appropriate). In the event
that the tumour starts to grow again, a biopsy might be taken if the patient
agrees to this at that time.

Previous clinical trials suggest that a combination of nivolumab and
ipilimumab could lead to a higher efficacy in a broad range of cancers,
including small cell lung carcinoma (SCLC). Ipilimumab is approved by the
Health Authorities in Europe, United States and Switzerland for the treatment
of malignant melanoma (a type of skin cancer), but at this moment not for small
cell lung carcinoma. Nivolumab has been approved for the treatment of malignant
melanoma by the Health Authorities in Europe, United States and Japan, but not
in Switzerland. Recently it was also approved for treatment of small cell lung
carcinoma in the Unites States (since March 2015) and in Europe (since July
2015). Consolidation therapy (combination of nivolumab and ipilimumab)
following the standard treatment might increase overall survival in patients
with small cell lung carcinoma.

The most common side effects of nivolumab and ipilimumab are immune-related and
generally medically manageable with topical and/or systemic immunosuppressants.
Special attention will be given to a possible enhancement of pulmonary toxicity
due to ipilimumab. A safety evaluation will take place 12 weeks after the first
30 patients have been randomised into the experimental arm (total of 60
patients, 30 in the nivolumab plus ipilimumab combination and 30 in the
observation arm).

In summary, the combination of ipilimumab and nivolumab offers a significant
survival benefit to patients with advanced melanoma and evidence of clinical
activity in randomised studies in other tumour types, including small cell lung
carcinoma. These findings, together with evidence of a safety profile that is
manageable with careful monitoring and appropriate intervention for treatment
of immune-mediated toxicities, suggest a favourable benefit to risk ratio.