A randomized, double-blind, placebo-controlled, phase III study evaluating the efficacy and safety of pembrolizumab plus platinum-based doublet chemotherapy with or without canakinumab as first line therapy for locally advanced or metastatic non-squamous and squamous non-small cell lung cancer subjects (CANOPY-1)

Pembrolizumab in combination with platinum-based doublet chemotherapy is
recently been approved as first line treatment for locally advanced or
metastatic non-small cell lung cancer (NSCLC) and will soon be taken up in the
Dutch treatment guidelines as standard first line treatment.
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).

Primary:
Safety run-in part (part 1):
• Recommended Phase 3 dose regimen (RP3R) of canakinumab in combination with
pembrolizumab plus chemotherapy.
Double-blind, randomized, placebo-controlled part (part 2):
• Progressive free survival (PFS) between the two treatment arms
• Overall survival (OS) between the two treatment arms.
Secondary:
Safety run-in part (part 1): pharmacokinetics, safety and tolerability,
immunogenicity (anti-drug antibodies) of canakinumab and pembrolizumab,
preliminary clinical anti-tumor activity (overall response rate (ORR), disease
control rate (DCR) and duration of response (DOR)).
Double-blind, randomized, placebo-controlled part (part 2): ORR, DCR, time to
response (TTR) and DOR, safety, pharmacokinetics, immunogenicity, patient
reported outcomes.

The study consists of 2 parts: the safety run-in part (part 1, n=27) and a
double-blind, randomized, placebo controlled part (part 2, n=600).
Part 1: open label part to determine RP3R of canakinumab in combination with
pembrolizumab and chemotherapy.
Part 2: double-blind, randomized, placebo-controlled part to evaluate the
efficacy and safety of canakinumab vs. placebo in combination with
pembrolizumab plus chemotherapy.
First line treatment for advanced disease.
Treatment until disease progression or unacceptable toxicity.
Treatment cycles of 3 weeks.
Canakinumab: 200 mg S.C. every 3 (or 6) weeks. In part 2 randomization (1:1) to
canakinumab 200 mg S.C. or placebo.
Pembrolizumab 200 mg I.V. infusions every 3 weeks (max. 35 cycles).
Chemotherapy part 1: 3 cohorts:
• Cohort A (for non-squamous NSCLC): carboplatin plus pemetrexed I.V.infusions
• Cohort B (for non-squamous NSCLC): cisplatin plus pemetrexed I.V. infusions
• Cohort C (for squamous or non-squamous NSCLC): carboplatin plus paclitaxel
I.V. infusions.
Chemotherapy for part 2:
• For non-squamous NSCLC: carboplatin or cisplatin plus pemetrexed I.V.
infusions
• For squamous NSCLC: carboplatin plus paclitaxel or nab-paclitaxel I.V.
infusions.

Part 1: Treatment with canakinumab, pembrolizumab and chemotherapy.
Part 2: Treatment with canakinumab or placebo, pembrolizumab and chemotherapy.

Risk: Adverse effects of study treatment.
Burden:
Screening 4 weeks.
Treatment:
Canakinumab (or placebo): subcutaneous injection (1 mL) every 3 weeks until
disease progression.
Pembrolizumab: I.V. infusion 500 mL every 3 weeks (max. 35 cycles)
Chemotherapy: 2 agents I.V. infusion 500 mL every 3 weeks (max. 4 cycles).
Study procedures (based on treatment duration of 18 cycles):
Physical examination: 23.
Blood tests: 29, in total approx. 452 mL (part 1) and 674 mL (part 2).
Tumor biopsy: 0-1.
Pregnancy test (if relevant): 23.
ECG: 1-2.
CT/MRI scan(s): approx. 7 (in line with standard treatment).
Questionnaires: 19.
Optional: blood test cytokines (10 mL), blood test genetic research (6 mL),
tumor biopsy (1-2).