Ignite Creation Date:
2024-05-05 @ 9:07 PM
Last Modification Date:
2024-10-26 @ 9:59 AM
Study NCT ID:
NCT00816868
Status:
COMPLETED
Last Update Posted:
2012-03-01
First Post:
2009-01-02
Brief Title:
A Phase II Study of TX Regimen as First-line Treatment for Asian Elderly Patients With Advanced Adenocarcinoma of Lung
Sponsor:
Sun Yat-sen University
Organization:
Sun Yat-sen University
Study Overview
Official Title:
A Phase II Study of Erlotinib in Combination With Capecitabine as First-line Treatment in Elderly Patients With Stage IIIBIV Adenocarcinoma Non-small Cell Lung Cancer NSCLC
Status:
COMPLETED
Status Verified Date:
2012-02
Last Known Status:
None
Delayed Posting:
No
If Stopped, Why?:
Not Stopped
Has Expanded Access:
False
If Expanded Access, NCT#:
N/A
Has Expanded Access, NCT# Status:
N/A
Acronym:
None
Brief Summary:
Because of the effect in the treatment of NSCLC the capecitabine and erlotinib may compose to a new regimen for NSCLC Based on the preclinical observation and the confirmed clinical synergistic anti-tumor activity of combined capecitabine and erlotinib in gemzar refractory advanced pancreatic cancer APC the investigators previously conducted a phase II study of erlotinib in combination with capecitabine against NSCLC
Detailed Description:
1 BACKGROUND AND RATIONALE 11 Background Lung cancer is the leading cause of cancer-related mortality in the world Non-small-cell lung cancer NSCLC the most common type of lung cancer comprises about 80 of all lung cancer cases and five-year survival across all stages is about 12 More than 60 of all NSCLC patients have advanced or metastatic disease that is not suitable for curative resection at diagnosis Platinum-based chemotherapy remains the cornerstone of treatment for these patients and results in a small but statistically significant improvement in survival compared with supportive care aloneBut the regimen is also associated with moderate to severe hematological and non-hematological toxic effects in a majority of patients
Approximately two-thirds of patients diagnosed with non-small cell lung cancer NSCLC are 65 years or older and nearly 50 are 70 years or older And greater than 90 of elderly patients experience a grade 34 toxicity when treated with a platinum-based doubletMoreovera group of patients with the performance status 2 is intolerant intravenous chemotherapy Availability of an effectiveless toxic therapy might help extend potentially beneficial treatment to a greater proportion of elderly or patients whose performance status 2
12 Rationale 121 Capecitabine for NSCLC Capecitabine is an oral prodrug of 5-FuIt is absorbed through the intestine and converted to 5-deoxy-S-fluorocytidine 5-DFCR by carboxylesterase and then to 5-deoxy-S-fluorouridine 5-DFUR by cytidine deaminase both steps taking place in the liver Finallyit is converted to the only active metabolite FU by thymidine phosphorylaseTP This occurs in both tumor and normal tissues however the TP is found at higher concentrations in some tumor tissue compared with normal healthy tissueThe expression of this enzymes may influence the effect of the capecitabine Han et al examined the TP expression in tumor tissue samples from NSCLC patients who enrolled in a previous phase II study of capecitabinedocetaxel chemotherapy and found that the patients with high tumour cell thymidine phosphorylase expression show a better response to capecitabine based chemotherapy
The thymidylate synthase TS is an important target enzyme for antifolate drugs such as 5-FUUFT and capecitabinebecause it catalyzes an essential step in DNA synthesis The predictive role of the expression of thymidylate synthase TS in tumors treated with antifolate drugs has been extensively reported in NSCLCIn 2006 Nakano et al performed an immunohistochemical study on the clinical significance of TS expression using 151 resected non-small-cell lung cancer NSCLC patients postoperatively treated with UFTThey found that the 5-year survival rate of patients with TS-negative tumours was significantly higher than that with TS-positive tumours P00133Miyoshi et al reported that the oral administration of UFT after surgery might improve the survival of NSCLC patients when TS levels in tumor tissues are lowwith the 5-year survival rates of patients positive and negative for TS were 500 and 895p0001Some research still found that TS expression was significantly higher in squamous cell carcinoma compared with adenocarcinoma when both mRNA levels and protein levels
Recentlya Phase III Study Comparing Cisplatin Plus Gemcitabine With Cisplatin Plus Pemetrexed in Chemotherapy-Naïve Patients With Advanced-Stage Non-Small- Cell Lung Cancer showed that Overall survival was statistically superior for cisplatin pemetrexed versus cisplatingemcitabine in patients with adenocarcinomaThe result reminded us that patients with adenocarcinoma were most likely to benefit from antifolate drugs
In the preclinical study we examined tumor specimens for TS and TP expression obtained from 171 Chinese NSCLC patients who were operated without any preoperative chemotherapy or radiation at our institute We categorized Grades 0 and 1 as negative Grades 2 and 3 as positive for both enzymes As for TS staining 146 n 25 were classified as Grade 0 287 n 49 as Grade 1 327 n 56 as Grade 2 and 240 n 41 as Grade 3 And for TP staining 123 n 21 were classified as Grade 0 170 n 29 as Grade 1 135 n 23 as Grade 2 and 573 n 98 as Grade 3 Although the anti-tumor activity of capecitabine has not been well evaluated in NSCLC the relatively high expression of TP 708 and low expression TS 433 in NSCLC provided a rationale for the use of capecitabine in patients with this tumor
122 Erlotinib for NSCLC Erlotinib is a novel small molecule inhibitor of the EGFR tyrosine kinase TK It has been approved as monotherapy for the treatment of patients with advanced NSCLC who have progressed following first- and second-line chemotherapyIt is fairly well tolerated and the salient adverse effects are mild to moderate skin rash and diarrhea And the further study showed that adenocarcinoma histology predicted the better survival
Recently a trial of erlotinib as first-line therapy in elderly patients has been reported by investigators at the Dana-Farber Cancer Center In 76 patients over the age of 70 the vast majority with adenocarcinoma histology the response rate was 12 and a median survival was 11 months
123 The synergistic interaction of erlotinib and capecitabine in NSCLC Giovannetti et al reported that erlotinib significantly reduced TS expression and activity possibly via E2F-1 reduction as detected by RT-PCR and western blot and the combination decreased TS in situ activity in NSCLC cells Furthermore Van SS et al found TS inhibitor 5-FU increases EGFR phosphorylation which potentially favors EGFR-TKIs activityThus erlotinib and capecitabine may have a strong synergism in NSCLC
Because of the effect in the treatment of NSCLC the capecitabine and erlotinib may compose to a new regimen for NSCLC Based on the preclinical observation and the confirmed clinical synergistic anti-tumor activity of combined capecitabine and erlotinib in gemzar refractory APC we previously conducted a phase II study of erlotinib in combination with capecitabine against NSCLC
Approximately two-thirds of patients diagnosed with non-small cell lung cancer NSCLC are 65 years or older and nearly 50 are 70 years or older And greater than 90 of elderly patients experience a grade 34 toxicity when treated with a platinum-based doubletMoreovera group of patients with the performance status 2 is intolerant intravenous chemotherapy Availability of an effectiveless toxic therapy might help extend potentially beneficial treatment to a greater proportion of elderly or patients whose performance status 2
12 Rationale 121 Capecitabine for NSCLC Capecitabine is an oral prodrug of 5-FuIt is absorbed through the intestine and converted to 5-deoxy-S-fluorocytidine 5-DFCR by carboxylesterase and then to 5-deoxy-S-fluorouridine 5-DFUR by cytidine deaminase both steps taking place in the liver Finallyit is converted to the only active metabolite FU by thymidine phosphorylaseTP This occurs in both tumor and normal tissues however the TP is found at higher concentrations in some tumor tissue compared with normal healthy tissueThe expression of this enzymes may influence the effect of the capecitabine Han et al examined the TP expression in tumor tissue samples from NSCLC patients who enrolled in a previous phase II study of capecitabinedocetaxel chemotherapy and found that the patients with high tumour cell thymidine phosphorylase expression show a better response to capecitabine based chemotherapy
The thymidylate synthase TS is an important target enzyme for antifolate drugs such as 5-FUUFT and capecitabinebecause it catalyzes an essential step in DNA synthesis The predictive role of the expression of thymidylate synthase TS in tumors treated with antifolate drugs has been extensively reported in NSCLCIn 2006 Nakano et al performed an immunohistochemical study on the clinical significance of TS expression using 151 resected non-small-cell lung cancer NSCLC patients postoperatively treated with UFTThey found that the 5-year survival rate of patients with TS-negative tumours was significantly higher than that with TS-positive tumours P00133Miyoshi et al reported that the oral administration of UFT after surgery might improve the survival of NSCLC patients when TS levels in tumor tissues are lowwith the 5-year survival rates of patients positive and negative for TS were 500 and 895p0001Some research still found that TS expression was significantly higher in squamous cell carcinoma compared with adenocarcinoma when both mRNA levels and protein levels
Recentlya Phase III Study Comparing Cisplatin Plus Gemcitabine With Cisplatin Plus Pemetrexed in Chemotherapy-Naïve Patients With Advanced-Stage Non-Small- Cell Lung Cancer showed that Overall survival was statistically superior for cisplatin pemetrexed versus cisplatingemcitabine in patients with adenocarcinomaThe result reminded us that patients with adenocarcinoma were most likely to benefit from antifolate drugs
In the preclinical study we examined tumor specimens for TS and TP expression obtained from 171 Chinese NSCLC patients who were operated without any preoperative chemotherapy or radiation at our institute We categorized Grades 0 and 1 as negative Grades 2 and 3 as positive for both enzymes As for TS staining 146 n 25 were classified as Grade 0 287 n 49 as Grade 1 327 n 56 as Grade 2 and 240 n 41 as Grade 3 And for TP staining 123 n 21 were classified as Grade 0 170 n 29 as Grade 1 135 n 23 as Grade 2 and 573 n 98 as Grade 3 Although the anti-tumor activity of capecitabine has not been well evaluated in NSCLC the relatively high expression of TP 708 and low expression TS 433 in NSCLC provided a rationale for the use of capecitabine in patients with this tumor
122 Erlotinib for NSCLC Erlotinib is a novel small molecule inhibitor of the EGFR tyrosine kinase TK It has been approved as monotherapy for the treatment of patients with advanced NSCLC who have progressed following first- and second-line chemotherapyIt is fairly well tolerated and the salient adverse effects are mild to moderate skin rash and diarrhea And the further study showed that adenocarcinoma histology predicted the better survival
Recently a trial of erlotinib as first-line therapy in elderly patients has been reported by investigators at the Dana-Farber Cancer Center In 76 patients over the age of 70 the vast majority with adenocarcinoma histology the response rate was 12 and a median survival was 11 months
123 The synergistic interaction of erlotinib and capecitabine in NSCLC Giovannetti et al reported that erlotinib significantly reduced TS expression and activity possibly via E2F-1 reduction as detected by RT-PCR and western blot and the combination decreased TS in situ activity in NSCLC cells Furthermore Van SS et al found TS inhibitor 5-FU increases EGFR phosphorylation which potentially favors EGFR-TKIs activityThus erlotinib and capecitabine may have a strong synergism in NSCLC
Because of the effect in the treatment of NSCLC the capecitabine and erlotinib may compose to a new regimen for NSCLC Based on the preclinical observation and the confirmed clinical synergistic anti-tumor activity of combined capecitabine and erlotinib in gemzar refractory APC we previously conducted a phase II study of erlotinib in combination with capecitabine against NSCLC
Study Oversight
Has Oversight DMC:
None
Is a FDA Regulated Drug?:
None
Is a FDA Regulated Device?:
None
Is an Unapproved Device?:
None
Is a PPSD?:
None
Is a US Export?:
None
Is an FDA AA801 Violation?:
None