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

Fadlo R. Khuri, James R. Rigas, Robert A. Figlin, Richard J. Gralla, Dong M. Shin, Reginald Munden, Nikolaus Fox, Mi Ra Huyghe, Yin Kean, Steven D. Reich, Waun K. Hong

Research output: Contribution to journalArticle

109 Citations (Scopus)

Abstract

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 bexaratene was escalated in cohorts of three patients from 150 mg/m2 to 600 mg/m2, beginning 1 week before the start of the cispiatin-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 bexaratene 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.

Original languageEnglish (US)
Pages (from-to)2626-2637
Number of pages12
JournalJournal of Clinical Oncology
Volume19
Issue number10
StatePublished - May 15 2001
Externally publishedYes

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Non-Small Cell Lung Carcinoma
Cisplatin
Survival
Maximum Tolerated Dose
Survival Rate
Retinoid X Receptors
Asthenia
Squamous Cell Neoplasms
bexarotene
vinorelbine
Prothrombin Time
Retinoids
Leukopenia
Lymphocyte Count
Pleural Effusion
Therapeutics
Amylases
Hyperlipidemias
Pancreatitis
Dyspnea

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite 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. / Khuri, Fadlo R.; Rigas, James R.; Figlin, Robert A.; Gralla, Richard J.; Shin, Dong M.; Munden, Reginald; Fox, Nikolaus; Huyghe, Mi Ra; Kean, Yin; Reich, Steven D.; Hong, Waun K.

In: Journal of Clinical Oncology, Vol. 19, No. 10, 15.05.2001, p. 2626-2637.

Research output: Contribution to journalArticle

Khuri, FR, Rigas, JR, Figlin, RA, Gralla, RJ, Shin, DM, Munden, R, Fox, N, Huyghe, MR, Kean, Y, Reich, SD & Hong, WK 2001, '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', Journal of Clinical Oncology, vol. 19, no. 10, pp. 2626-2637.
Khuri, Fadlo R. ; Rigas, James R. ; Figlin, Robert A. ; Gralla, Richard J. ; Shin, Dong M. ; Munden, Reginald ; Fox, Nikolaus ; Huyghe, Mi Ra ; Kean, Yin ; Reich, Steven D. ; Hong, Waun K. / 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. In: Journal of Clinical Oncology. 2001 ; Vol. 19, No. 10. pp. 2626-2637.
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title = "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",
abstract = "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 bexaratene was escalated in cohorts of three patients from 150 mg/m2 to 600 mg/m2, beginning 1 week before the start of the cispiatin-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 bexaratene 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.",
author = "Khuri, {Fadlo R.} and Rigas, {James R.} and Figlin, {Robert A.} and Gralla, {Richard J.} and Shin, {Dong M.} and Reginald Munden and Nikolaus Fox and Huyghe, {Mi Ra} and Yin Kean and Reich, {Steven D.} and Hong, {Waun K.}",
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T1 - 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

AU - Khuri, Fadlo R.

AU - Rigas, James R.

AU - Figlin, Robert A.

AU - Gralla, Richard J.

AU - Shin, Dong M.

AU - Munden, Reginald

AU - Fox, Nikolaus

AU - Huyghe, Mi Ra

AU - Kean, Yin

AU - Reich, Steven D.

AU - Hong, Waun K.

PY - 2001/5/15

Y1 - 2001/5/15

N2 - 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 bexaratene was escalated in cohorts of three patients from 150 mg/m2 to 600 mg/m2, beginning 1 week before the start of the cispiatin-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 bexaratene 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.

AB - 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 bexaratene was escalated in cohorts of three patients from 150 mg/m2 to 600 mg/m2, beginning 1 week before the start of the cispiatin-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 bexaratene 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.

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