A randomized, double-blind, placebo-controlled, phase III study evaluating the efficacy and safety of canakinumab in combination with docetaxel versus placebo in combination with docetaxel in subjects with non-small cell lung cancer (NSCLC) previously treated with PD-(L)1 inhibitors and platinum-based chemotherapy (CACZ885V2301, CANOPY-2)

The current standard second line treatment for locally advanced or metastatic
non-small cell lung cancer (NSCLC) is docetaxel.

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-1* (IL-1*) is one of the mediators of
pulmonary inflammation that can promote lung cancer.
Canakinumab is a human anti-IL-1* monoclonal antibody. Currently canakinumab is
approved and marketed as Ilaris for the treatment of various IL*1* 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-1* 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):
* to confirm tthe recommended Phase 3 dose regimen (RP3R) of canakinumab in
combination with docetaxel.
Double-blind, randomized, placebo-controlled part (part 2):
* to compare the overall survival (OS) between the two treatment arms
(canakinumab plus docetaxel vs. docetaxel).
Secondary:
Safety run-in part (part 1): pharmacokinetics, safety and tolerability,
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): progression free
survival (PFS), ORR, DCR, time to response (TTR) and DOR, safety,
pharmacokinetics, immunogenicity, ECOG performance status, patient reported
outcomes.

The study consists of 2 parts: the safety run-in part (part 1, n=6-18) and a
double-blind, randomized, placebo controlled part (part 2, n=226).
Part 1: open label part to determine RP3R of canakinumab in combination with
docetaxel.
Part 2: double-blind, randomized, placebo-controlled part to evaluate the
efficacy and safety of canakinumab vs. placebo in combination with docetaxel.
Second 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.
* Docetaxel: infusion every 3 weeks. Duration of infusion 1 hour.

Part 1: Treatment with canakinumab plus docetaxel
Part 2: Treatment with canakinumab or placebo plus docetaxel

Risk: Adverse effects of study treatment.
Burden:
Screening 4 weeks.
Treatment:
Canakinumab (or placebo): subcutaneous injection (1,5 mL) every 3 weeks until
disease progression.
Docetaxel: I.V. infusion 500 mL every 3 weeks.
Study procedures (based on treatment duration of 18 cycles):
Physical examination: 23.
Blood tests: 31, in total approx. 300 mL (part 1) and 516 mL (part 2).
Pregnancy test (if relevant): 23.
ECG: 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).