A randomized, open-label, phase II study of canakinumab or pembrolizumab as monotherapy or in combination as neoadjuvant therapy in subjects with resectable non-small cell lung cancer (CANOPY-N)

Non-small cell lung cancer (NSCLC) accounts for 85% of the lung cancer
diagnoses. About 30% of subjects have surgically resectable disease at
diagnosis. Surgery is the treatment of choice for subjects with NSCLC stages I
through IIIA. Five-year survival rates range from 50% for stage IA disease to
19% for stage IIIA disease, with most patients having postsurgical tumor
relapse. Despite apparently curative surgery, approximately 50% of stage IB and
70% of stage II NSCLC patients will relapse and eventually die of their disease.
Given the current limited survival of patients with NSCLC, even in early stages
of disease, new treatments options are needed.
Neoadjuvant and adjuvant treatments are used to eradicate micrometastatic
disease and minimize the risk of relapse. A meta-analysis involving 988
patients suggested that neoadjuvant chemotherapy improved five-year survival:
20% versus 14% without neoadjuvant chemotherapy. This improvement in survival
is similar to that observed in the meta-analyses of predominantly adjuvant.
Recent clinical studies demonstrated promising results of immunotherapy
treatment in the neoadjuvant setting.
Chronic inflammation plays an important role in the development of NSCLC. Key
etiological risk factors such as smoking, second-hand smoke exposure, chronic
infections, and exposure to environmental toxins cause a chronic inflammatory
milieu that plays a critical role in carcinogenesis, particularly, in lung
cancer. The cytokine interleukin-1β (IL-1β) is one of the mediators of
pulmonary inflammation that promotes lung cancer.
Canakinumab is a human anti-IL-1β monoclonal antibody. Currently canakinumab is
approved and marketed as Ilaris for the treatment of various IL*1β driven
auto-inflammatory diseases, such as gouty arthritis and Systemic Juvenile
Idiopathic Arthritis.
In the CANTOS study (a cardiovascular study) canakinumab reduced, in addition
to the composite end point of stroke and myocardial infarction, the occurrence
of lung cancer and lung cancer mortality compared to placebo in a
dose-dependent manner. One hypothesis to explain these findings is that
canakinumab reduced the rate of progression, invasiveness and metastatic spread
of already existing tumors, which were too small to be detected at study entry.
This data along with the preclinical information that IL-1β supports
tumorigenic inflammation provides the rationale to investigate the therapeutic
role of canakinumab in non-small cell lung cancer (NSCLC).
In the current study we will test the effects of canakinumab, pembrolizumab
(Keytruda, a PD-1 blocking drug) and the combination of both drugs as
neoadjuvant treatment for stage IB-IIIA NSCLC patients.

Primary:
• To assess the Major Pathological Response (MPR) rate (<= 10% of residual
viable tumor cells) on the resected specimen at the time of surgery in all
subjects randomized to canakinumab alone or in combination with pembrolizumab.
Secondary:
• To assess overall response rate (ORR) in randomized subjects treated with
canakinumab or pembrolizumab as monotherapy or in combination.
• To assess surgical feasibility rate in each treatment arm based on randomized
subjects.
• To assess the MPR rate of at the time of surgery in (a) all subjects
randozmised to pembrolizumab monotherapy arm, (b) all randomized subjects based
on local review in each treatment arm, (c) to estimate the difference in MPR
and posterior probability of the difference in MPR >= 10% between canakinumab +
pembrolizumab combination and pembrolizumab alone
• To assess the prevalence and incidence of immunogenicity (IG) anti-drug
antibodies (ADA) of canakinumab and pembrolizumab
• To assess the pharmacokinetics (PK) of canakinumab and pembrolizumab as
monotherapy and in combination.
• To evaluate safety and tolerability of canakinumab and pembrolizumab as
monotherapy and in combination.
• To assess the relationship between key blood or tissue based biomarkers and
MPR.

Phase II, randomized, open-label study evaluating efficacy and safety of
canakinumab and pembrolizumab monotherapy or the combination of both drugs as
neoadjuvant treatment. Approximately 110 subjects (~100 evaluable subjects)
will be randomized in a 2:2:1 ratio to one of the treatment arms (canakinumab
alone or canakinumab in combination with pembrolizumab or pembrolizumab alone).
Randomization will be stratified by histology (squamous vs non-squamous).
Subjects will receive 2 doses of canakinumab (200 mg s.c. Q3W) alone or in
combination with pembrolizumab or two doses of pembrolizumab as single agent
(200 mg i.v. Q3W).

Treatment with canakinumab alone, pembrolizumab alone or the combination of
both drugs.

Risk: Adverse effects of study treatment.
Burden:
7 visits (excluding surgery) and 2 telephone calls.
Screening 4 weeks.
Treatment:
Canakinumab (or placebo): subcutaneous injection (1 mL) every 3 weeks until
disease progression.
Pembrolizumab: I.V. infusion every 3 weeks (max. 35 cycles)
Study procedures:
Physical examination: 7.
Blood tests: 7, in total approx. 320 mL.
Tumor biopsy: 1-2.
Pregnancy test (if relevant): 7.
ECG: 1.
PET-CT scan(s): Not standard of care, PET-CT to examine the effect of the study
treatment, within 7 days prior to the surgery.
Optional: Trial Feedback Questionnaire 2 times; use of personal data and
biological samples for future research.