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E-46. Phase II trials of promising chemopreventive agents
S56
E-46.
Phase II Trials of Promising Chemopreventive Agents
Stephen Lam ‘, Annette McWilliams ’ Lung
Cancer
Prevention
Program
‘, Jean 1eRiche I, Calum MacAulay
& Cancer Imaging Depaninent, Bn’tish Columbia Cancer 2 UT Southwestern Medical Center; Dallas, Texas, USA
Randomised controlled clinical trials in prevention of lung cancer have been applied in healthy high-risk smokers (primary prevention), in subjects with pre-malignant lesions (secondary prevention), and in the prevention of second primary lung cancers (tertiary prevention). After two decades of clinical research, chemoprevention of lung cancer is proving difficult and frustrating. A non-toxic and effective chemopreventive agent has not yet been identified. A number of new agents are currently undergoing or will be undergoing clinical trial. Phase III chemoprevention trials using lung cancer incidence as the primary endpoint usually involve thousands of subjects and take 7 to 10 years to complete. Before embarking on these studies, it would be important to first evaluate these agents in smaller and shorter Phase II clinical trials. Another issue when evaluating potential agents is how to identify the minority of smokers or ex-smokers who would truly benefit from chemoprevention since the cumulative lifetime risk for lung cancer in smokers is less than 20%. To determine the usefulness of sputum atypia as a biomarker to identify those at highest risk for lung cancer, image analysis of sputum cells was performed in 561 volunteer smokers 250 years of age with a smoking history of >30 pack-years. Seventy percent of the subjects were found to have sputum atypia as defined by the presence of ~5 cells with a DNA index > 1.2 times that of normal non-cycling cells. Ninety-three percent of the subjects with lung cancer and 94% of those with moderate/severe dysplasia on LIFE bronchoscopy had sputum atypia. In comparison, using a newly reported risk assessment index proposed by Bach et al. [l], if we used a lo-year lung cancer risk of ~2% that would identify 93% of those with lung cancer in the same cohort as a criterion to screen subjects for participation, we would have enrolled more subjects without lung cancer (85% versus 70%) into a chemoprevention/early detection study. Using autofluorescence bronchoscopy to localise the number and size of dysplastic lesions in smokers with sputum atypia, we have evaluated several promising chemopreventive agents in randomised, placebo-controlled trials using histopathology as the surrogate endpoint biomarker. One such agent, anethole dithiolethione (ADT), in a dosage of 25 mg orally TID for 6 months, was found to result in a significant reduction in the appearance of new dysplastic lesions as well as a reduction in progression of pre-existing dysplastic lesions compared to placebo [2]. ADT acts predominantly by increasing the expression or activity of phase II enzymes, such as glutathione-S-transferase, and acts as an antioxidant. In vitro, ADT also inhibits NFKB activation. ADT is an approved drug that has been used in Canada, Europe, and
‘, Adi Gazdar2
Agency,
Vancouver;
Canada;
other countries to treat drug- and radiation-induced hyposalivation as well as xerostomia due to other causes. Its choleretic property would make it particularly attractive for further tertiary prevention trials in patients with head and neck cancers. Inflammation is recognised as a critical component of tumorigenesis. In an animal model of lung cancer, inhaled budesonide was found to be a potent chemopreventive agent [3-51. We have recently completed a Phase II trial of inhaled budesonide versus placebo in volunteer smokers with bronchial dysplasia. 1043 current/former smokers 40-74 years of age with a smoking history of 230 pack-years were screened with image analysis of sputum cells. Sixty-six percent of them were found to have sputum atypia by image analysis. Eighty-two percent agreed to have autofluorescence bronchoscopy and 50% of those were found to have ~1 site of bronchial dysplasia. One hundred and twelve subjects were randomised to receive either budesonide at a dose of 800 mcg twice daily by inhalation (Pulmicort Turbuhaler) or its placebo for 6 months. All subjects received a repeat bronchoscopy and biopsy as well as bronchoalveolar lavage for measurement of PGE2 and 15-HETE in the BAL fluids. The results of the study are being analysed and will be presented. Advances in in-vitro and in-vivo imaging technologies have made it possible to identify subjects at highest risk of lung cancer and to evaluate the potential efficacy of promising agents in short-term Phase II chemoprevention trials before proceeding to large-scale primary prevention studies. Supported by U.S. NC1 contracts NOI-CN-65030 and NOlCN-85188. References [II Bach PB, PI
[31
[41
[51
Kattan MW, Thomquist MD, Kris MG, Tate RC, Bamett MJ, Hsieh LJ, Begg CB. Variations in lung cancer risk among smokers. J Nat1 Cancer Inst 2003;95(6):470-478. Lam S, MacAulay C, 1eRiche JC, Dyachkova Y, Coldman A, Guillaud M, Hawk E, Christen MO, Gazdar AE A randomized phase IIb trial of anethole dithiolethione in smokers with bronchial dysplasia. J Nat1 Cancer Inst 2002; 94(13):100-1009. Wattenberg LW, Wiedmann TS, Estensen RD, Zimmerman CL, Steele VE, Kelloff GJ. Cbemoprevention of pulmonary carcinogenesis by aerosolized budesonide in female A/J mice. Cancer Res, 1997; 57:5489-92. Wattenberg LW, Estensen RD. Studies of chemopreventive effects of budenoside on benzo[a]pyreneinduced neoplasia of the lung of female A/J mice. Carcinogenesis, 1997; 18:2015-7. Wattenberg LW, Wiedmann TS, Estensen RD, Zimmerman CI, Galbraitb AR, Steele VE, Kelloff Gj. Chemoprevention of pulmonary carcinogenesis by brief exposures to aerosolized budesonide or beclomethasone dipmpionate and by the combination of aerosolized budesonide and dietary myo-inositol. Carcinogenesis 2000; 21: 179-182.
E-46.
Phase II Trials of Promising Chemopreventive Agents
Stephen Lam ‘, Annette McWilliams ’ Lung
Cancer
Prevention
Program
‘, Jean 1eRiche I, Calum MacAulay
& Cancer Imaging Depaninent, Bn’tish Columbia Cancer 2 UT Southwestern Medical Center; Dallas, Texas, USA
Randomised controlled clinical trials in prevention of lung cancer have been applied in healthy high-risk smokers (primary prevention), in subjects with pre-malignant lesions (secondary prevention), and in the prevention of second primary lung cancers (tertiary prevention). After two decades of clinical research, chemoprevention of lung cancer is proving difficult and frustrating. A non-toxic and effective chemopreventive agent has not yet been identified. A number of new agents are currently undergoing or will be undergoing clinical trial. Phase III chemoprevention trials using lung cancer incidence as the primary endpoint usually involve thousands of subjects and take 7 to 10 years to complete. Before embarking on these studies, it would be important to first evaluate these agents in smaller and shorter Phase II clinical trials. Another issue when evaluating potential agents is how to identify the minority of smokers or ex-smokers who would truly benefit from chemoprevention since the cumulative lifetime risk for lung cancer in smokers is less than 20%. To determine the usefulness of sputum atypia as a biomarker to identify those at highest risk for lung cancer, image analysis of sputum cells was performed in 561 volunteer smokers 250 years of age with a smoking history of >30 pack-years. Seventy percent of the subjects were found to have sputum atypia as defined by the presence of ~5 cells with a DNA index > 1.2 times that of normal non-cycling cells. Ninety-three percent of the subjects with lung cancer and 94% of those with moderate/severe dysplasia on LIFE bronchoscopy had sputum atypia. In comparison, using a newly reported risk assessment index proposed by Bach et al. [l], if we used a lo-year lung cancer risk of ~2% that would identify 93% of those with lung cancer in the same cohort as a criterion to screen subjects for participation, we would have enrolled more subjects without lung cancer (85% versus 70%) into a chemoprevention/early detection study. Using autofluorescence bronchoscopy to localise the number and size of dysplastic lesions in smokers with sputum atypia, we have evaluated several promising chemopreventive agents in randomised, placebo-controlled trials using histopathology as the surrogate endpoint biomarker. One such agent, anethole dithiolethione (ADT), in a dosage of 25 mg orally TID for 6 months, was found to result in a significant reduction in the appearance of new dysplastic lesions as well as a reduction in progression of pre-existing dysplastic lesions compared to placebo [2]. ADT acts predominantly by increasing the expression or activity of phase II enzymes, such as glutathione-S-transferase, and acts as an antioxidant. In vitro, ADT also inhibits NFKB activation. ADT is an approved drug that has been used in Canada, Europe, and
‘, Adi Gazdar2
Agency,
Vancouver;
Canada;
other countries to treat drug- and radiation-induced hyposalivation as well as xerostomia due to other causes. Its choleretic property would make it particularly attractive for further tertiary prevention trials in patients with head and neck cancers. Inflammation is recognised as a critical component of tumorigenesis. In an animal model of lung cancer, inhaled budesonide was found to be a potent chemopreventive agent [3-51. We have recently completed a Phase II trial of inhaled budesonide versus placebo in volunteer smokers with bronchial dysplasia. 1043 current/former smokers 40-74 years of age with a smoking history of 230 pack-years were screened with image analysis of sputum cells. Sixty-six percent of them were found to have sputum atypia by image analysis. Eighty-two percent agreed to have autofluorescence bronchoscopy and 50% of those were found to have ~1 site of bronchial dysplasia. One hundred and twelve subjects were randomised to receive either budesonide at a dose of 800 mcg twice daily by inhalation (Pulmicort Turbuhaler) or its placebo for 6 months. All subjects received a repeat bronchoscopy and biopsy as well as bronchoalveolar lavage for measurement of PGE2 and 15-HETE in the BAL fluids. The results of the study are being analysed and will be presented. Advances in in-vitro and in-vivo imaging technologies have made it possible to identify subjects at highest risk of lung cancer and to evaluate the potential efficacy of promising agents in short-term Phase II chemoprevention trials before proceeding to large-scale primary prevention studies. Supported by U.S. NC1 contracts NOI-CN-65030 and NOlCN-85188. References [II Bach PB, PI
[31
[41
[51
Kattan MW, Thomquist MD, Kris MG, Tate RC, Bamett MJ, Hsieh LJ, Begg CB. Variations in lung cancer risk among smokers. J Nat1 Cancer Inst 2003;95(6):470-478. Lam S, MacAulay C, 1eRiche JC, Dyachkova Y, Coldman A, Guillaud M, Hawk E, Christen MO, Gazdar AE A randomized phase IIb trial of anethole dithiolethione in smokers with bronchial dysplasia. J Nat1 Cancer Inst 2002; 94(13):100-1009. Wattenberg LW, Wiedmann TS, Estensen RD, Zimmerman CL, Steele VE, Kelloff GJ. Cbemoprevention of pulmonary carcinogenesis by aerosolized budesonide in female A/J mice. Cancer Res, 1997; 57:5489-92. Wattenberg LW, Estensen RD. Studies of chemopreventive effects of budenoside on benzo[a]pyreneinduced neoplasia of the lung of female A/J mice. Carcinogenesis, 1997; 18:2015-7. Wattenberg LW, Wiedmann TS, Estensen RD, Zimmerman CI, Galbraitb AR, Steele VE, Kelloff Gj. Chemoprevention of pulmonary carcinogenesis by brief exposures to aerosolized budesonide or beclomethasone dipmpionate and by the combination of aerosolized budesonide and dietary myo-inositol. Carcinogenesis 2000; 21: 179-182.