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 Biomarker

• Status: Unknown status
• Trial end date: 2013-09-01
• Target enrollment: 0
• Participant gender: All

Summary

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 B2 expression in 6 of 60 tumor samples analyzed; however, all samples expressed RAR B2 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.

• Phase: Phase 3
• Accepts Healthy Volunteers?: No

Details

• Lead Sponsor: National Institute of Cancerología
• Treatments: Albumin-Bound Paclitaxel; Cisplatin; Paclitaxel; Tretinoin

Criteria

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,

• Creatinine purification > 75 ml per min,

• Those 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.