Trial Information

Cox-2-Inhibitor and Chemotherapy in Non-Small Cell Lung Cancer. A Prospective Randomized Double-Blind Study

The study (CYCLUS trial, CY-cyclooxygenase-2 inhibitor, Chemotherapy, LUng cancer, Survival)
is a prospective randomized double-blind multicenter trial. Patients are randomized to
receive celecoxib at a dose of 400 mg b.i.d. or placebo. Primary endpoint of the trial is
survival. Secondary endpoints are: quality of life, progression-free survival, toxicity,
cardiovascular events, and biological parameters (plasma VEGF and proteomics).

The rationale behind the study consists of preclinical observations of antitumor effect of
celecoxib in NSCLC. Inhibition of angiogenesis and proliferation as well as increased
apoptosis has been demonstrated. In addition, pilot studies have shown that the combination
of chemotherapy and celecoxib is feasible. No unexpected toxicity has been recorded in such
trials. Furthermore, a randomized study of indomethacin, prednisolone or placebo in other
types of advanced cancer, mainly gastrointestinal, showed a survival advantage for patients
receiving antiinflammatory treatment.

Chemotherapy is given according to the current standard of the participating institution. In
practice, patients will usually receive either carboplatin + gemcitabine or carboplatin +
vinorelbine. Treatment duration with chemotherapy is 4 cycles (cycle length 3 weeks) in the
absence of tumour progression or prohibitive toxicity.

Treatment with the study drug starts on the first day of cancer chemotherapy. Maximum
treatment duration is one year. Treatment will be stopped earlier in case of objective tumor
progression, serious toxicity that is considered to be related to the study drug or if the
patient wants to stop treatment.

The size of the study is based on the hypothesis that celecoxib could prolong median
survival by 8 weeks as compared to 7.5 months in the placebo group. With standard
statistical requirements (type I error 5%, type II error 20%), the calculated number of
patients was 760.

The study was supported by the Swedish Lung Cancer Study Group and organized as a
multicenter trial, with participation of seven university hospitals and six smaller
hospitals. The number of new cases of NSCLC stage IIIB-IV and performance status 0-2 in
Sweden is around 1200/year. It was expected that 20% of the patients could be included in
the study, which would make completion possible in three years.

The study was opened for randomization on May 31, 2006. Recruitment of patients was lower
than expected. The study was closed for further randomization on May 31, 2009, as originally
planned. 319 patients were included. Since maximum duration of treatment with the study drug
is one year, the code will be broken after May 31, 2010. Data analysis is planned to take
place in summer and autumn, 2010.