This Article Full Text Full Text (PDF) Purchase Article View Shopping Cart Alert me when this article is cited Alert me if a correction is posted Services Email this article to a colleague Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Save to my personal folders Download to citation manager Rights & Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Khuri, F. R. Articles by Hong, W. K. Search for Related Content PubMed PubMed Citation Articles by Khuri, F. R. Articles by Hong, W. K. Social Bookmarking                            What's this?

Multi-Institutional Phase I/II Trial of Oral Bexarotene in Combination With Cisplatin and Vinorelbine in Previously Untreated Patients With Advanced Non–Small-Cell Lung Cancer

From the Departments of Thoracic/Head and Neck Medical Oncology and Diagnostic Radiology, University of Texas M.D. Anderson Cancer Center, Houston, TX; Dartmouth-Hitchcock Medical Center, Lebanon, NH; Jonsson Comprehensive Cancer Center, University of California Los Angeles, Los Angeles; Ligand Pharmaceuticals, Inc, San Diego, CA; and Department of Medical Oncology, Ochsner Clinic, New Orleans, LA.

Address reprint requests to Fadlo R. Khuri, MD, Department of Thoracic/Head and Neck Medical Oncology, University of Texas M.D. Anderson Cancer Center, 1515 Holcombe Blvd, Box 80, Houston, TX 77030; email: fkhuri{at}mdanderson.org

PURPOSE: Bexarotene (Targretin; Ligand Pharmaceuticals, Inc, San Diego, CA) is a retinoid-X-receptor (RXR)-selective retinoid with preclinical antitumor activity in squamous cell cancers. In this phase I/II trial, we combined bexarotene with cisplatin and vinorelbine in the treatment of patients with non–small-cell lung cancer (NSCLC).

PATIENTS AND METHODS: Forty-three patients who had stage IIIB NSCLC with pleural effusion or stage IV NSCLC and had received no prior therapy received bexarotene in combination with cisplatin (100 mg/m²) and vinorelbine (alternating doses of 30 mg/m² and 15 mg/m²). In the phase I portion, the daily dose of bexarotene was escalated in cohorts of three patients from 150 mg/m² to 600 mg/m², beginning 1 week before the start of the cisplatin-vinorelbine regimen. Once the maximum-tolerated dose (MTD) of bexarotene was determined, the study entered the phase II portion. Response rate was the primary end point; median survival time and 1-year survival rate were secondary end points.

RESULTS: In the phase I portion, the daily MTD of bexarotene was determined to be 400 mg/m². Eight of 43 patients exhibited major responses. Seven (25%) of the 28 patients in the phase II portion responded to treatment. The median survival time in the phase II portion was 14 months; nine (32%) of the 28 patients were still alive at a minimum follow-up of 2 years. One-year and projected 3-year survival rates were 61% and 30%, respectively. The most common grade 3 and 4 adverse events were hyperlipemia, leukopenia, nausea, vomiting, pneumonia, dyspnea, anemia, and asthenia. Grade 3 and 4 laboratory abnormalities with incidences greater than 5% were decreased hemoglobin levels and WBC, absolute neutrophil, and absolute lymphocyte counts and increased prothrombin time and creatinine and amylase levels. Of the two cases of pancreatitis, one required hospitalization and both were associated with increased triglyceride levels. There was one death secondary to renal insufficiency unrelated to bexarotene treatment.

CONCLUSION: In patients with advanced NSCLC, bexarotene with cisplatin and vinorelbine yielded acceptable phase II response rates (25%) and was associated with better-than-expected survival (14-month median survival time; 61% 1-year, 32% 2-year, and 30% projected 3-year survival rates). The regimen should be studied in larger clinical trials.

CiteULike    Complore    Connotea    Del.icio.us    Digg    Facebook    Reddit    Technorati    Twitter    What's this?

This article has been cited by other articles:

				K. Liby, C. C. Black, D. B. Royce, C. R. Williams, R. Risingsong, M. M. Yore, X. Liu, T. Honda, G. W. Gribble, W. W. Lamph, et al. The rexinoid LG100268 and the synthetic triterpenoid CDDO-methyl amide are more potent than erlotinib for prevention of mouse lung carcinogenesis Mol. Cancer Ther., May 1, 2008; 7(5): 1251 - 1257. [Abstract] [Full Text] [PDF]

				G. R. Blumenschein Jr, F. R. Khuri, J. von Pawel, U. Gatzemeier, W. H. Miller Jr, R. M. Jotte, J. Le Treut, S.-L. Sun, J. K. Zhang, Z. E. Dziewanowska, et al. Phase III Trial Comparing Carboplatin, Paclitaxel, and Bexarotene With Carboplatin and Paclitaxel in Chemotherapy-Naive Patients With Advanced or Metastatic Non-Small-Cell Lung Cancer: SPIRIT II J. Clin. Oncol., April 10, 2008; 26(11): 1879 - 1885. [Abstract] [Full Text] [PDF]

				R. Ramlau, P. Zatloukal, J. Jassem, P. Schwarzenberger, S. V. Orlov, M. Gottfried, J. R. Pereira, G. Temperley, R. Negro-Vilar, S. Rahal, et al. Randomized Phase III Trial Comparing Bexarotene (L1069-49)/Cisplatin/Vinorelbine With Cisplatin/Vinorelbine in Chemotherapy-Naive Patients With Advanced or Metastatic Non-Small-Cell Lung Cancer: SPIRIT I J. Clin. Oncol., April 10, 2008; 26(11): 1886 - 1892. [Abstract] [Full Text] [PDF]

				K. Liby, D. B. Royce, R. Risingsong, C. R. Williams, M. D. Wood, R. A. Chandraratna, and M. B. Sporn A New Rexinoid, NRX194204, Prevents Carcinogenesis in Both the Lung and Mammary Gland Clin. Cancer Res., October 15, 2007; 13(20): 6237 - 6243. [Abstract] [Full Text] [PDF]

				T. Tanaka, K. S. Suh, A. M. Lo, and L. M. De Luca p21WAF1/CIP1 Is a Common Transcriptional Target of Retinoid Receptors: PLEIOTROPIC REGULATORY MECHANISM THROUGH RETINOIC ACID RECEPTOR (RAR)/RETINOID X RECEPTOR (RXR) HETERODIMER AND RXR/RXR HOMODIMER J. Biol. Chem., October 12, 2007; 282(41): 29987 - 29997. [Abstract] [Full Text] [PDF]

				K. H. Dragnev, W. J. Petty, S. J. Shah, L. D. Lewis, C. C. Black, V. Memoli, W. C. Nugent, T. Hermann, A. Negro-Vilar, J. R. Rigas, et al. A Proof-of-Principle Clinical Trial of Bexarotene in Patients with Non-Small Cell Lung Cancer Clin. Cancer Res., March 15, 2007; 13(6): 1794 - 1800. [Abstract] [Full Text] [PDF]

				W. M. Golden, K. B. Weber, T. L. Hernandez, S. I. Sherman, W. W. Woodmansee, and B. R. Haugen Single-Dose Rexinoid Rapidly and Specifically Suppresses Serum Thyrotropin in Normal Subjects J. Clin. Endocrinol. Metab., January 1, 2007; 92(1): 124 - 130. [Abstract] [Full Text] [PDF]

				R. Govindan, J. Crowley, L. Schwartzberg, P. Kennedy, C. Williams, B. Ekstrand, A. Sandler, D. Jaunakais, V. Bolejack, and R. Ghalie Phase II Trial of Bexarotene Capsules in Patients With Advanced Non-Small-Cell Lung Cancer After Failure of Two or More Previous Therapies J. Clin. Oncol., October 20, 2006; 24(30): 4848 - 4854. [Abstract] [Full Text] [PDF]

				J.-Z. Zeng, D.-F. Sun, L. Wang, X. Cao, J.-B. Qi, T. Yang, C.-Q. Hu, W. Liu, and X.-K. Zhang Hypericum sampsonii induces apoptosis and nuclear export of retinoid X receptor-alpha Carcinogenesis, October 1, 2006; 27(10): 1991 - 2000. [Abstract] [Full Text] [PDF]

				F. R. Khuri, J. J. Lee, S. M. Lippman, E. S. Kim, J. S. Cooper, S. E. Benner, R. Winn, T. F. Pajak, B. Williams, G. Shenouda, et al. Randomized Phase III Trial of Low-dose Isotretinoin for Prevention of Second Primary Tumors in Stage I and II Head and Neck Cancer Patients. J Natl Cancer Inst, April 5, 2006; 98(7): 441 - 450. [Abstract] [Full Text] [PDF]

				K. H. Dragnev, W. J. Petty, S. Shah, A. Biddle, N. B. Desai, V. Memoli, J. R. Rigas, and E. Dmitrovsky Bexarotene and Erlotinib for Aerodigestive Tract Cancer J. Clin. Oncol., December 1, 2005; 23(34): 8757 - 8764. [Abstract] [Full Text] [PDF]

				M. J. Edelman, R. Smith, P. Hausner, L. A. Doyle, K. Kalra, J. Kendall, M. Bedor, and S. Bisaccia Phase II Trial of the Novel Retinoid, Bexarotene, and Gemcitabine Plus Carboplatin in Advanced Non-Small-Cell Lung Cancer J. Clin. Oncol., August 20, 2005; 23(24): 5774 - 5778. [Abstract] [Full Text] [PDF]

				W.-C. Yen and W. W. Lamph The selective retinoid X receptor agonist bexarotene (LGD1069, Targretin) prevents and overcomes multidrug resistance in advanced breast carcinoma Mol. Cancer Ther., May 1, 2005; 4(5): 824 - 834. [Abstract] [Full Text] [PDF]

				J. R. Rigas and K. H. Dragnev Emerging Role of Rexinoids in Non-Small Cell Lung Cancer: Focus on Bexarotene Oncologist, January 1, 2005; 10(1): 22 - 33. [Abstract] [Full Text] [PDF]

				W.-C. Yen, M. R. Corpuz, R. Y. Prudente, T. A. Cooke, R. P. Bissonnette, A. Negro-Vilar, and W. W. Lamph A Selective Retinoid X Receptor Agonist Bexarotene (Targretin) Prevents and Overcomes Acquired Paclitaxel (Taxol) Resistance in Human Non-Small Cell Lung Cancer Clin. Cancer Res., December 15, 2004; 10(24): 8656 - 8664. [Abstract] [Full Text] [PDF]

				M. Konopleva, E. Elstner, T. J. McQueen, T. Tsao, A. Sudarikov, W. Hu, W. D. Schober, R.-Y. Wang, D. Chism, S. M. Kornblau, et al. Peroxisome proliferator-activated receptor {gamma} and retinoid X receptor ligands are potent inducers of differentiation and apoptosis in leukemias Mol. Cancer Ther., October 1, 2004; 3(10): 1249 - 1262. [Abstract] [Full Text] [PDF]

				F. J. Esteva, J. Glaspy, S. Baidas, L. Laufman, L. Hutchins, M. Dickler, D. Tripathy, R. Cohen, A. DeMichele, R. C. Yocum, et al. Multicenter Phase II Study of Oral Bexarotene for Patients With Metastatic Breast Cancer J. Clin. Oncol., March 15, 2003; 21(6): 999 - 1006. [Abstract] [Full Text] [PDF]

				K. H. Dragnev, D. Stover, and E. Dmitrovsky Lung Cancer Prevention: The Guidelines Chest, January 1, 2003; 123(1_suppl): 60S - 71S. [Abstract] [Full Text] [PDF]

				J. T. Trent, P. Romanelli, and F. A. Kerdel Topical Targretin and Intralesional Interferon Alfa for Cutaneous Lymphoma of the Scalp Arch Dermatol, November 1, 2002; 138(11): 1421 - 1423. [Full Text] [PDF]

				S. Liu, K. M. Ogilvie, K. Klausing, M. A. Lawson, D. Jolley, D. Li, J. Bilakovics, B. Pascual, N. Hein, M. Urcan, et al. Mechanism of Selective Retinoid X Receptor Agonist-Induced Hypothyroidism in the Rat Endocrinology, August 1, 2002; 143(8): 2880 - 2885. [Abstract] [Full Text] [PDF]

				M. A. Smith and B. Anderson Where to Next with Retinoids for Cancer Therapy? Clin. Cancer Res., October 1, 2001; 7(10): 2955 - 2957. [Full Text] [PDF]