Ignite Creation Date:
2024-05-05 @ 12:09 PM
Last Modification Date:
2024-10-26 @ 9:21 AM
Study NCT ID:
NCT00259675
Status:
COMPLETED
Last Update Posted:
2007-11-15
First Post:
2005-11-28
Brief Title:
Alternating Cycles of CarboplatinGemcitabine and CarboplatinTaxol for Advanced Stage NSCLC
Sponsor:
University of Saskatchewan
Organization:
University of Saskatchewan
Study Overview
Official Title:
Treatment of Stages IIIB and IV Non Small Cell Lung Cancer With Alternating Cycles of CarboplatinTaxol and CarboplatinGemcitabine
Status:
COMPLETED
Status Verified Date:
2007-05
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:
To see the efficacy of using chemotherapies alternatively carboplatin and gemcitabine alternating with carboplatin and taxol for pts with stage IIIB nonresectable and stage IV NSCLC
Detailed Description:
Lung cancer is the leading cause of cancer death in men and women in the USA and account for 28 of all cancer deaths in 2002 1 In stage IV and some patients with stage III disease chemotherapy is widely used with the primary aim of prolonging survival and or palliating symptoms A meta analysis of clinical studies that randomized patients between the best supportive care and chemotherapy concluded that Cisplatin based chemotherapy resulted in a potential gain in the median survival and an increase of the 1-year survival rate compared to the supportive care alone 2 Combination chemotherapy regimens PlatinumTaxanes PlatinumGemcitabine PlatinumVinca alkaloids have demonstrated a response rate of 30-50 with median survival of approximately 10 months one year survival rates around 40 and 2 year survival of only 10 in patients with advanced Non Small Cell Lung Cancer NSCLC 34 Therefore it is important to continue to search for new agentscombinations that can be used to improve the overall prognosis of these patients
Rationale for using alternating cycles of chemotherapies
Emergence of progressive or recurrent disease is a consequence of selection and overgrowth of pre-existent drug resistant cells during treatment Based on the mechanism of somatic cell mutation Goldie and Coldman 56 proposed a model for the emergence of drug resistant cells in tumors Their model proposed that alternating non-cross-resistant combinations would prevent the overgrowth of resistant cancer cells and improve the probability of tumor control or cure Their recommendation assumed that the two non-cross-resistant regimens were of equal or similar efficacy and that the drugs contained in the two combinations could not be administered together in one single regimen
There are few instances in Clinical Oncology where two regimens of similar efficacy exist for the same tumor type Since apparently equivalent chemotherapy regimens exist for the treatment of NSCLC the Goldie and Coldman hypothesis could also be tested in this tumor type Historically SWOG conducted a phase III trial randomizing patients between FOMi 5-FluorouracilVincristineMitomycinC CAP CyclophosphamideDoxorubicinCisplatin and a third arm FOMiCAP which alternated the two combinations Response rates were 26 17 and 22 respectively and were not statistically significantly different P0 247 Survival was reported as 20 24 and 23 weeks respectively Statistically survival of FOMiCAP treated patients was superior to FOMi treated P0024 but not CAP treated P023 patients 7 Since then several studies have attempted to improve upon the response rate and survival in advanced NSCLC by using regimens with alternating cycles of non-cross-resistant therapy 891011 These regimens yielded overall response rate of 21-49 median survival of 20-48 wks with acceptable toxicity
Though several studies have been done to evaluate clinical response in lung cancer using alternating chemotherapies none of these studies have evaluated clinical response with alternating Paclitaxel and Gemcitabine based treatment which are two of the most effective chemotherapy regimens in use currently In studies of Platinum combinations that included one of these agents results were better than those achieved with Platinum alone or combined with earlier generation agents such as Vindesine or Etoposide 12 Current evidence suggests that combinations of Paclitaxel or Gemcitabine with Cisplatin or Carboplatin are among the most active palliative treatments for advanced NSCLC With combination of Cisplatin and Gemcitabine a response rate in phase II trials ranged from 30-54 with median survival times of approximately 8-15 months and I year survival rates from 34-61 1314 Myelosuppression was the major toxicity while Cisplatin associated nonhematologic gastrointestinal renal and neurologic effects were also problematic Attempts to reduce toxicity associated with the Cisplatin Gemcitabine regimen have included replacing Cisplatin with Carboplatin a platinum analog possessing similar efficacy and hematologic effects but lacking the non hematologic toxicity commonly experienced with Cisplatin therapy 1516 Furthermore Carboplatin can be administered with no need for prehydration to avoid renal toxicity
In several phase II studies of the CarboplatinGemcitabine regimen in patients with stages IIIB and IV NSCLC objective response rate ranged from 25-59 with median survival of 10-16 months 1718 In a phase II trial Carrato et al 19 compared 21 day and 28-day schedules of the GemcitabineCarboplatin regimen in 75 advanced NSCLC patients Patients received Gemcitabine 1000mgm2 on days 18 and 15 with Carboplatin AUC 5 on day 1 every 28 days or a modified regimen omitting the day 15 Gemcitabine dose and repeating cycles every 21 days Incidence of grades 3 and 4 neutropenia were 52 and 38 respectively with the 28 day regimen and decreased to 39 and 23 with the modified regimen Significant reductions in rates of grades 3 and 4 thrombocytopenia were noted from 45 and 61 respectively in the 28 day cohort to 24 P004 and 17 P0002 respectively in the 21 day group Response rate 46 and 37 respectively and median survival time 38 wks for both schedules were maintained in both groups of patients Furthermore higher dose intensities of both Gemcitabine and Carboplatin were achieved every 3 wk vs every 4 wk schedules Gemcitabine 1133 v 1002 mgwk Carboplatin 162 v 124 mgwk 20 Results from current phase III trials 2122 are also consistent in showing good activity and tolerability of the CarboplatinGemcitabine combination in advanced NSCLC and establish this regimen as an appealing approach for treating this disease On the basis of above discussion we have chosen CarboplatinGemcitabine as one of the doublets we will use in our study The other doublet we are using in our study is CarboplatinPaclitaxel Several studies have shown response rate of approximately 30 with median survival 8-11 months 232425 Toxicity was mild Grades 34 neutropenia thrombocytopenia and anemia were seen in 15 2 and 5 respectively 25 Dose finding studies 2627 of Paclitaxel and Carboplatin in advanced NSCLC have shown that doses of Paclitaxel higher than 175 mgm2 prolongs the median time to progression but causes more neurotoxicity and leucopenia Also better response rate the longer overall and better one-year survival seen with the higher dose of Paclitaxel were not statistically significant
Rationale for using Gemcitabine and Paclitaxel alternatively in the same regimen for NSCLC is provided by their antitumor activity different mechanism of cytotoxicity and different toxicity profiles In an in-vitro study 28 Jensen PB et al has shown collateral sensitivity between Paclitaxel and Gemcitabine in seven resistant small cell lung cancer cell lines
The importance of evaluating the impact of any therapy on the quality of life QOL of patients with malignancy has been demonstrated in recent literature 29 Patients with advanced NSCLC suffer from a variety of treatment related challenges and do not have an expectation of cure Hence it is particularly important to compare treatment alternatives not only on survival endpoints but also on QOL Therefore we propose to incorporate QOL evaluations in the proposed clinical trial QOL instrument we are using is the FACT-L version 4 The FACT-L is a validated 36-item Likert instrument that combines both relative frequency of symptomaticquality of life problems with the patients perceived relative importance of each issue 30
Can we use Taxotere as second line agent if patient had received Paclitaxel as first line agent
In comparison with best supportive care Docetaxel Taxotere has shown a benefit in overall survival for the second line treatment of NSCLC 3132 Patients with prior exposure to paclitaxel were excluded from TAX 317 trial 29 But in TAX 320 trial 30 many patients had received Paclitaxel prior to enrollment 31 of patients in Docetaxel 100 mg arm 42 of patients in the Docetaxel 75 mg arm and 41 of patients in the control arm Authors were able to evaluate retrospectively what impact if any prior Paclitaxel exposure may have had on response and survival with Docetaxel Partial response rates were equivalent in the cohort of 91 patients who had received prior Paclitaxel 105 and the group of 157 patients who had not received prior Paclitaxel 85 In a similar analysis of survival data prior Paclitaxel therapy had no bearing on the survival advantage seen with Docetaxel
Rationale for using alternating cycles of chemotherapies
Emergence of progressive or recurrent disease is a consequence of selection and overgrowth of pre-existent drug resistant cells during treatment Based on the mechanism of somatic cell mutation Goldie and Coldman 56 proposed a model for the emergence of drug resistant cells in tumors Their model proposed that alternating non-cross-resistant combinations would prevent the overgrowth of resistant cancer cells and improve the probability of tumor control or cure Their recommendation assumed that the two non-cross-resistant regimens were of equal or similar efficacy and that the drugs contained in the two combinations could not be administered together in one single regimen
There are few instances in Clinical Oncology where two regimens of similar efficacy exist for the same tumor type Since apparently equivalent chemotherapy regimens exist for the treatment of NSCLC the Goldie and Coldman hypothesis could also be tested in this tumor type Historically SWOG conducted a phase III trial randomizing patients between FOMi 5-FluorouracilVincristineMitomycinC CAP CyclophosphamideDoxorubicinCisplatin and a third arm FOMiCAP which alternated the two combinations Response rates were 26 17 and 22 respectively and were not statistically significantly different P0 247 Survival was reported as 20 24 and 23 weeks respectively Statistically survival of FOMiCAP treated patients was superior to FOMi treated P0024 but not CAP treated P023 patients 7 Since then several studies have attempted to improve upon the response rate and survival in advanced NSCLC by using regimens with alternating cycles of non-cross-resistant therapy 891011 These regimens yielded overall response rate of 21-49 median survival of 20-48 wks with acceptable toxicity
Though several studies have been done to evaluate clinical response in lung cancer using alternating chemotherapies none of these studies have evaluated clinical response with alternating Paclitaxel and Gemcitabine based treatment which are two of the most effective chemotherapy regimens in use currently In studies of Platinum combinations that included one of these agents results were better than those achieved with Platinum alone or combined with earlier generation agents such as Vindesine or Etoposide 12 Current evidence suggests that combinations of Paclitaxel or Gemcitabine with Cisplatin or Carboplatin are among the most active palliative treatments for advanced NSCLC With combination of Cisplatin and Gemcitabine a response rate in phase II trials ranged from 30-54 with median survival times of approximately 8-15 months and I year survival rates from 34-61 1314 Myelosuppression was the major toxicity while Cisplatin associated nonhematologic gastrointestinal renal and neurologic effects were also problematic Attempts to reduce toxicity associated with the Cisplatin Gemcitabine regimen have included replacing Cisplatin with Carboplatin a platinum analog possessing similar efficacy and hematologic effects but lacking the non hematologic toxicity commonly experienced with Cisplatin therapy 1516 Furthermore Carboplatin can be administered with no need for prehydration to avoid renal toxicity
In several phase II studies of the CarboplatinGemcitabine regimen in patients with stages IIIB and IV NSCLC objective response rate ranged from 25-59 with median survival of 10-16 months 1718 In a phase II trial Carrato et al 19 compared 21 day and 28-day schedules of the GemcitabineCarboplatin regimen in 75 advanced NSCLC patients Patients received Gemcitabine 1000mgm2 on days 18 and 15 with Carboplatin AUC 5 on day 1 every 28 days or a modified regimen omitting the day 15 Gemcitabine dose and repeating cycles every 21 days Incidence of grades 3 and 4 neutropenia were 52 and 38 respectively with the 28 day regimen and decreased to 39 and 23 with the modified regimen Significant reductions in rates of grades 3 and 4 thrombocytopenia were noted from 45 and 61 respectively in the 28 day cohort to 24 P004 and 17 P0002 respectively in the 21 day group Response rate 46 and 37 respectively and median survival time 38 wks for both schedules were maintained in both groups of patients Furthermore higher dose intensities of both Gemcitabine and Carboplatin were achieved every 3 wk vs every 4 wk schedules Gemcitabine 1133 v 1002 mgwk Carboplatin 162 v 124 mgwk 20 Results from current phase III trials 2122 are also consistent in showing good activity and tolerability of the CarboplatinGemcitabine combination in advanced NSCLC and establish this regimen as an appealing approach for treating this disease On the basis of above discussion we have chosen CarboplatinGemcitabine as one of the doublets we will use in our study The other doublet we are using in our study is CarboplatinPaclitaxel Several studies have shown response rate of approximately 30 with median survival 8-11 months 232425 Toxicity was mild Grades 34 neutropenia thrombocytopenia and anemia were seen in 15 2 and 5 respectively 25 Dose finding studies 2627 of Paclitaxel and Carboplatin in advanced NSCLC have shown that doses of Paclitaxel higher than 175 mgm2 prolongs the median time to progression but causes more neurotoxicity and leucopenia Also better response rate the longer overall and better one-year survival seen with the higher dose of Paclitaxel were not statistically significant
Rationale for using Gemcitabine and Paclitaxel alternatively in the same regimen for NSCLC is provided by their antitumor activity different mechanism of cytotoxicity and different toxicity profiles In an in-vitro study 28 Jensen PB et al has shown collateral sensitivity between Paclitaxel and Gemcitabine in seven resistant small cell lung cancer cell lines
The importance of evaluating the impact of any therapy on the quality of life QOL of patients with malignancy has been demonstrated in recent literature 29 Patients with advanced NSCLC suffer from a variety of treatment related challenges and do not have an expectation of cure Hence it is particularly important to compare treatment alternatives not only on survival endpoints but also on QOL Therefore we propose to incorporate QOL evaluations in the proposed clinical trial QOL instrument we are using is the FACT-L version 4 The FACT-L is a validated 36-item Likert instrument that combines both relative frequency of symptomaticquality of life problems with the patients perceived relative importance of each issue 30
Can we use Taxotere as second line agent if patient had received Paclitaxel as first line agent
In comparison with best supportive care Docetaxel Taxotere has shown a benefit in overall survival for the second line treatment of NSCLC 3132 Patients with prior exposure to paclitaxel were excluded from TAX 317 trial 29 But in TAX 320 trial 30 many patients had received Paclitaxel prior to enrollment 31 of patients in Docetaxel 100 mg arm 42 of patients in the Docetaxel 75 mg arm and 41 of patients in the control arm Authors were able to evaluate retrospectively what impact if any prior Paclitaxel exposure may have had on response and survival with Docetaxel Partial response rates were equivalent in the cohort of 91 patients who had received prior Paclitaxel 105 and the group of 157 patients who had not received prior Paclitaxel 85 In a similar analysis of survival data prior Paclitaxel therapy had no bearing on the survival advantage seen with Docetaxel
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