Trial Information

Randomized Phase III Trial: Effect of All-trans Retinoic Acid With Chemotherapy Based on Paclitaxel and Cisplatin As First-line Treatment of Patients With Advanced Non-small Cell Lung Cancer and Expression of RAR-alfa and RAR-beta as Response Biomarkers

BACKGROUND Platinum-based chemotherapy (CT) is the standard treatment for advanced
non-small-cell lung cancer (NSCLC). Unfortunately, the survival and response rate (RR) to CT
is poor. There is great interest in new treatment strategies. One of this new strategies
include the use of retinoids such as atRA. The synergistic effect of cytotoxic agents with
retinoids has been demonstrated in lung cancer. At the INCan, our work group carried out a
phase II study trial that included 107 patients with advanced NSCLC. They were randomized to
receive atRA (20-mg/m2) or placebo combined with 80 mg/m2 of cisplatin and 175 mg/m2 of
paclitaxel. The results showed a significant increase in the RR of the atRA group, reaching
55.8% ( 95% CI; 46.6-64.9%) compared with 25.4% (95% CI, 21.3-29.5%; p = 0.001) in patients
who received placebo. Median Progression-free survival (PFS) in the atRA group was 8.9
months, while for those of placebo, PFS was 6.0 months (p = 0.008). There were no
significant differences in the grade 3-4 side effects between groups, except for
hypertriglycemia, which presented with greater frequency in the atRA group (p = 0.05).
Immunohistochemical stains determine the RAR beta 2 expression in 6 of 60 tumor samples
analyzed; however, all samples expressed RAR beta 2 in adjacent normal tissue.

HYPOTHESIS Patients with NSCLC who receive the scheme combined with first-line CT plus 45
mg/m2 of atRA will have a greater PFS and RR to CT with an acceptable toxicological profile.

OBJECTIVES

1. Obtain a greater RR to CT and PFS in patients with advanced NSCLC who receive
cisplatin- and paclitaxel-based CT combined with a 45-mg/m2 daily dose of atRA with an
acceptable toxicological profile .

2. Evaluate the benefit of RAR beta and RAR alfa expression as a response biomarker.

METHODS Three hundred and thirty patients with advanced NSCLC will be included to receive
Paclitaxel 175 mg/m2 and Cisplatin 80 mg/m2 (PC) every 21 days for 6 cycles. Patients will
be randomized to receive ATRA 45 mg2/day or placebo 1 week before treatment until completing
six cycles. Imaging studies will be performed prior and after two cycles of CT to assess
response. RAR beta and RAR alfa expression will be analyzed by immunohistochemistry in lung
tumoral tissue and in the adjacent lung tissue.

POPULATON AND SAMPLE

The institutions that will recruit patients will be the National Institute of Cancerology
(INCan) and the National Institute of Respiratory Diseases (INER) according to the inclusion
and exclusion criteria of the protocol:

Inclusion criteria: Patients with advanced NSCLC (stages III B or IV according to the
Tumor node metastasis [TNM] classification) who receive paclitaxel 175 mg/m2- and
cisplatin-based palliative therapy every 3 weeks during 4 cycles; general status with a
Karnofsky score of ≥70%, Eastern Cooperative Oncology Group (ECOG) ≤2, hepatic and hematic
cytology tests within normal ranges, and creatinine purification >75 ml per min, who
accepted to participate in the study, and who signed the letter of informed consent.

Exclusion criteria: Patients with comorbidity with another type of cancer who refuse to
enter the protocol; patients who require reduction of the chemotherapy dose due to
alterations in their laboratory examinations; patients with a poor general health state;
absence of histological diagnosis, and previous treatment with chemotherapy.

Statistical analysis With the purpose of description, the continuous variables will be
expressed as arithmetic means, medians, and Standard deviations (SDs), the variable
categories as proportions and 95% confidence intervals (95% CIs). Inferential comparisons
will be conducted by means of the Student t test or the Mann-Whitney U test according to
data distribution (normal and non-normal, respectively) determined by the Kolmogorov-Smirnov
test, for example, comparison of age means between both groups. The X2 test or the Fisher
exact test will be employed to evaluate significance among categorical variables, for
example, both groups (atRA vs. placebo) of ECOG higher or lower than 80, stage IIIB vs. IV,
history of smoking, RAR expression, and response. Statistical significance will be
determined as a p value (p <0.05) with a two-tailed test. PFS and GS times will be
determined from day of initiation of chemotherapy until date of death, respectively, and
will be analyzed by the Kaplan-Meier test. Comparisons between groups will be performed with
the log-rank test. All variables were dichotomized analyses of the survival curves.
Adjustment for potential confounders will be performed by means of Cox proportion
multivariate regression analysis. The SPSS version 15 (SPSS, Inc., Chicago, IL, USA)
software package will be used for data analysis.