Trial Information

A Phase II Trial of the Addition of Ipilimumab to Carboplatin and Etoposide Chemotherapy for the First Line Treatment of Extensive Stage Small Cell Lung Cancer (ICE)

A Phase II trial of the addition of Ipilimumab to Carboplatin and Etoposide chemotherapy for
the first line treatment of extensive stage small cell lung cancer (ICE)

Indication:

Extensive Stage Small cell lung cancer

Primary Objective:

To establish the progression free survival at 1 year in patients with extensive stage small
cell lung cancer treated with ipilimumab, carboplatin and etoposide.

Secondary Objective:

To assess the response to and toxicity of the combination of ipilimumab with carboplatin and
etoposide chemotherapy.

Immunological Objectives:

1. To examine whether ipilimumab stimulates a humoral immune response to onco-neuronal
self-antigens

The results from the above measurement of antibodies against onco-neuronal antigens
will be used to focus the cellular biomarker analysis and identify targets to assess
cellular responses:

2. To measure the effect of ipilimumab on CD8+ T-cells directed against onco-neuronal
antigens, presumed to be responsible for the desired cytotoxic activity against cancer
cells.

3. To evaluate the immune response to non-neuronal antigens in the presence of ipilimumab.

Rationale:

Small cell lung cancer accounts for around 20% of all lung cancer presentation in the UK. Of
these approximately half present with extensive disease, overall representing 4000 new cases
annually. Although initial response to chemotherapy for this group of patients ranges from
50-60% 1, 2, subsequent relapse is inevitable and results in poor survival with only 5% of
patients alive at 2 years from diagnosis.

Despite attempts to improve on conventional chemotherapy with platinum and etoposide in
extensive stage small cell lung cancer, neither modification of conventional
chemotherapeutic drugs, nor the use of novel targeted therapy has shown an increased
benefit. A conceptual change in therapeutic strategy is therefore required, and
immunotherapy is an attractive avenue to pursue.

Anti-CTLA4 antibody may allow the development or induction of anti-tumour immunity even in
the absence of a known tumour antigen and without active anti-tumour vaccination.
Chemotherapy effectively kills tumour cells and releases tumour derived antigens and as such
administration of anti-CTL4 antibody may induce a clinically useful anti-tumour immune
response against these antigens.

This trial will therefore investigate the addition of the anti-CTLA4 antibody ipilimumab to
conventional carboplatin and etoposide chemotherapy in extensive stage small cell lung
cancer.

Trial Design:

Single stage non-randomised phase II trial

Sample size:

Patients will be recruited so that 40 patients are treated with chemo-immunotherapy. If 8 or
more patients are progression free at 1 year the treatment will be considered to be
successful and warrant further testing.

Study Population:

All patients consented will form the ITT population.

• Patients who have received at least 1 dose of Ipilimumab will form the analysis population
(N=40).

Dosage Regimen/Duration of Treatment:

Subjects will receive up to 6 cycles of carboplatin and etoposide chemotherapy according to
response and toxicity. Carboplatin will be administered at a dose of AUC = 6 (calculated
according to the Calvert formula using a Cockcroft and Gault calculation of creatinine
clearance) IV, day 1.

Etoposide will be administered at 120mg/m2 IV day 1, 100mg BD PO days 2 and 3. Both
chemotherapy drugs will be delivered as a 21 day cycle (q21) with up to a maximum of 6
cycles delivered according to response unless progressive disease (RECIST) and or excessive
toxicity.

Ipilimumab will be administered at a dose of 10mg/kg IV on day 1 of cycles 3-6 of
chemotherapy.

In the absence of immune related progression of disease or unacceptable toxicity, subsequent
maintenance doses of ipilimumab will be delivered every 12 weeks starting at week 30 at a
dose of 10 mg/kg until unacceptable toxicity or immune related disease progression.

Tumour assessments:

Tumour assessments by CT scanning of the chest, abdomen and pelvis will be performed at
baseline and the following time points until progression:

Weeks 6, 12, 18, 24, 30, 36, 42, 48, 52 and then 12 weekly until progression by both RECIST
and immune related response criteria.

Duration of study:

It is expected that with the current standard of care the trial will take 24 months to
recruit with completion of the trial anticipated in 3 years. The study may however continue
for longer if patients are continuing to receive maintenance ipilimumab, in which case the
study will finish 100 days after the last dose of ipilimumab (when it is clear the last dose
has been given) or when all patients have died.

Safety monitoring:

Given the different safety profile of ipilimumab and carboplatin / etoposide chemotherapy,
no overlapping toxicity is expected.

However, throughout the trial, there will be a close monitoring of the nature and the
severity of the adverse events reported on an on-going basis.

A planned interim safety monitoring assessment will be performed. Once 9 patients have been
treated with the combination for at least 6 weeks (subjects who discontinued treatment
earlier due to excessive toxicity of chemo-immunotherapy will also be considered), a first
clinical safety assessment will be performed to identify any early safety signals from
ipilimumab given in combination with carboplatin and etoposide.

In addition a review of safety may be triggered throughout the trial:

If greater than or equal to 40% of subjects treated develop a greater than or equal to Grade
3 toxicity thought to be related to the study drugs; or If greater than or equal to 10% of
subjects experience an unexpected ipilimumab-related greater than or equal to Grade 3
toxicity that cannot be alleviated or controlled by appropriate care and/or steroid and/or
infliximab therapy within 14 days of the initiation of such therapy.

In response to any ipilimumab-related deaths unless attributed to disease progression.

In these circumstances the data will be carefully reviewed to determine the appropriate
course of action, which could include:

Continue without modification; Continue with modifications of the study protocol.
Modifications may include, but are not limited to, changes in inclusion/exclusion criteria,
frequency of safety monitoring, change in ipilimumab dose, and alterations in study
procedures; Discontinue the study (with provisions for orderly discontinuation in accordance
with good medical practice) under extreme circumstances (eg, insufficient benefit-to-risk
effect of the experimental treatment).

The decision to put patient accrual on hold while reviewing safety data will be taken or
not, based on characteristics of the serious adverse events reported on an ongoing basis.

The review will take into account the known toxicity profile for ipilimumab and for
carboplatin/etoposide, and the potential association of immune-related Adverse Events
(irAEs) with clinical efficacy.