Ignite Creation Date:
2024-05-05 @ 12:04 PM
Last Modification Date:
2024-10-26 @ 9:19 AM
Study NCT ID:
NCT00231855
Status:
COMPLETED
Last Update Posted:
2012-04-24
First Post:
2005-09-30
Brief Title:
Efficacy Study of Weekly Taxotere and Topotecan for Recurrent Gynecologic GYN Cancers
Sponsor:
Montefiore Medical Center
Organization:
Montefiore Medical Center
Study Overview
Official Title:
Phase II Trial- Weekly Taxotere and Topotecan for Recurrent Ovarian Primary Peritoneal Endometrial and Uterine Cancers
Status:
COMPLETED
Status Verified Date:
2012-04
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:
The primary aim of this study is
To determine the overall clinical response rate of weekly Topotecan and Taxotere in women with recurrent ovarian primary peritoneal endometrial and uterine cancers
The secondary aims of this study are
To evaluate the safety and tolerability of the combination therapy with weekly Topotecan and Taxotere in patients with recurrent ovarian primary peritoneal endometrial or uterine cancers
To determine the progression free survival and overall survival in women treated with weekly Topotecan and Taxotere in patients with recurrent ovarian primary peritoneal endometrial and uterine cancers who have been previously treated with chemotherapy andor radiation therapy
To determine the overall clinical response rate of weekly Topotecan and Taxotere in women with recurrent ovarian primary peritoneal endometrial and uterine cancers
The secondary aims of this study are
To evaluate the safety and tolerability of the combination therapy with weekly Topotecan and Taxotere in patients with recurrent ovarian primary peritoneal endometrial or uterine cancers
To determine the progression free survival and overall survival in women treated with weekly Topotecan and Taxotere in patients with recurrent ovarian primary peritoneal endometrial and uterine cancers who have been previously treated with chemotherapy andor radiation therapy
Detailed Description:
Endometrial carcinoma is the most common gynecologic cancer accounting for 6500 deaths in 2002 in the United States There has been a 128 increase in endometrial cancer deaths over the past decade mainly due to recurrences Although primary surgery with or without adjuvant therapy can cure most patients effective therapy for those patients with advanced or recurrent disease is needed Due to the advanced age of this patient population and associated medical comorbidities these patients are not always ideal candidates for experimental therapies exploring dose intensity or toxic agents Treatment options for advanced or recurrent disease are limited Cytotoxic therapy has made little impact on survival
Recent data has demonstrated efficacy of Topotecan in advanced or recurrent endometrial cancer A Phase II trial performed primarily by the New York Gynecologic Oncology Group through ECOG found Topotecan to be an active first line treatment for metastatic or recurrent endometrial cancer The overall response rate was 20 with 340 patients complete responders A Phase II trial by the Gynecologic Oncology Group GOG of 29 patients with advanced or recurrent endometrial cancer reported a 10 overall response rate to 5-day intravenous Topotecan However 55 of patients had stable disease Reported side effects were mainly hematologic specifically neutropenia and thrombocytopenia Finkler and Holloway reported a phase III trial using weekly Topotecan in recurrent endometrial cancer 23 of patients had partial response to therapy with a decrease in grade 4 neutropenia and thrombocytopenia compared to the 5-day infusion In a pilot study examining the role of 5-day Topotecan in uterine papillary serous carcinoma UPSC Chambers et al report 11 of 12 patients who received Topotecan as front-line therapy to be disease-free at 13 months median follow-up Anemia and neutropenia were managed effectively with hematopoietic stimulating factors
Taxanes have also been reported to be effective in the treatment of advanced and recurrent endometrial cancer Endometrial cancer cell lines have demonstrated sensitivity to paclitaxel Response rates of 35-37 have been reported in two separate phase II trials Günthert et al reported a complete response to Taxotere in a patient with recurrent endometrial cancer
Taxotere is an agent well documented in the management of advanced ovarian cancer with a response rate of approximately 30 in platinum-refractory patients Taxotere has also demonstrated clinical response in patients classified as paclitaxel-refractory confirming an incomplete cross-resistance between these two agents Based on these data there is reason to believe that the combination of Topotecan and Taxotere in the second-line setting may prove promising in patients initially treated with paclitaxel and platinum-based therapy
Topotecan and Taxotere have known activity in ovarian cancer patients Recent weekly dosing schedules suggest similar activity in ovarian cancer patients with less toxicity Ovarian cancer patients who have significant Taxane-related side effects including neuropathy do well with weekly Taxotere Both Topotecan and Taxotere have documented efficacy in recurrent endometrial cancer but no study to date has utilized them in combination for the treatment of endometrial cancer In addition to utilizing this regimen in a phase II setting for recurrent ovarian cancer we propose a phase II trial utilizing this combination for the treatment of recurrent endometrial cancer The justification for including all of these tumor types in the same protocol is the known similar response rates of these Gynecologic tumors to all chemotherapies The endpoints and power are designed for all of the histologic types but subset analysis will be used for each tumor type after completion of the trial
Because of the broad spectrum of antitumor activity of both Topotecan and Taxotere several phase III trials have been conducted with this combination regimen Lu and colleagues at MD Anderson administered docetaxel Taxotere intravenously on Day 1 followed by bolus daily intravenous Topotecan on days 1-3 with subcutaneous Neupogen Filgrastim support on days 4-13 Dose limiting toxicity for the regimen was febrile neutropenia and the recommended dose for phase II trials was docetaxel 75 mgm2 IV on day 1 and topotecan 14 mgm2 IV on days 1-3 with Neupogen filgrastim 5 mcgkgd SC on days 4-13 Three of the 11 patients enrolled experienced a response with the combination 1 CR and 1 PR in nasopharynx cancer and 1 PR in SCLC Aijaz and colleagues at New York Medical Center conducted a similar pilot study in patients with recurrent ovarian and primary peritoneal cancer In this trial all of the patients received docetaxel 80 mgm2 IV on day 1 and topotecan 10 mgm2 IV on days 1-5 The patients also received Neupogen filgrastim 10-mcgkg beginning on day 6 and continuing until the neutrophil count recovered to 10000mL The regimen was relatively well tolerated with neutropenia being the most frequently reported side effect Preliminary antitumor activity was impressive with 1 complete response 4 partial responses and 4 stable diseases reported among the twelve patients enrolled in the pilot study A final phase I study combining topotecan and docetaxel was also conducted at The University of Wisconsin by Stella and colleagues In this trial docetaxel was administered IV on day 1 followed by daily IV bolus Topotecan on days 1-5 In contrast to the previous studies prophylactic growth factor support was not administered following chemotherapy administration Because of significant myelosuppression at the initial dose level the protocol was amended and the starting dose of Topotecan was reduced As expected the dose-limiting toxicity was myelosuppression consisting of both neutropenia and thrombocytopenia The maximum tolerated dose for the combination regimen was docetaxel 60 mgm2 IV on day 1 followed by Topotecan 075 mgm2d on days 1-5
Recently the combination of Topotecan and Taxotere has been used in a Phase I setting in platinum sensitive patients with recurrent ovarian and primary peritoneal cancers Eleven patients have been treated to date with weekly docetaxel 30 mgm2wk plus topotecan 35 mgm2wk Two patients were non-evaluable one due to rapidly progressive disease and one due to noncompliance Of the nine evaluable patients five patients experienced dose-limiting toxicities as follows
1 cycle 1 day 15 C1D15 held due to platelets 33K in a heavily pretreated patient including previous oxaliplatin
2 C1D15 dose decreased due to grade 3 diarrhea
3 C1D8 held due to grade 3-4 nausea and vomiting may have been disease related
4 C1D15 held due to platelets 49 K 74 yo heavily pretreated including previous XRT
5 C1D15 held due to platelets 43K and declining creatinine clearance of 43 mlmin 3 prior regimens including XRT PS 2 and history of thrombocytopenia
One additional patient is planned to complete this dose level to provide 10 evaluable patients Of the 36 patients receiving 76 cycles of therapy myelosuppression was brief and reversible with no febrile neutropenia Per verbal communication from Dr Burris the recommended phase II dose will be docetaxel 30 mgm2wk plus topotecan 35 mgm2wk on days 1 8 and 15 every 28 days for minimally pretreated patients
In addition to possible synergy with this combination of drugs in other tumor types the weekly dosing may have a better safety profile The dose-limiting toxicity for Topotecan when administered on a daily x 5-administration schedule is myelosuppression However when the drug is administered on a weekly administration schedule the myelosuppression is ameliorated and is no longer dose limiting Additionally weekly docetaxel administration is gaining in popularity in the clinical arena due to the improved toxicity profile of the drug The possibility of synergy with the improved safety profile secondary to weekly dosing makes this combined dosing regimen a rational possibility for this patient population
Recent data has demonstrated efficacy of Topotecan in advanced or recurrent endometrial cancer A Phase II trial performed primarily by the New York Gynecologic Oncology Group through ECOG found Topotecan to be an active first line treatment for metastatic or recurrent endometrial cancer The overall response rate was 20 with 340 patients complete responders A Phase II trial by the Gynecologic Oncology Group GOG of 29 patients with advanced or recurrent endometrial cancer reported a 10 overall response rate to 5-day intravenous Topotecan However 55 of patients had stable disease Reported side effects were mainly hematologic specifically neutropenia and thrombocytopenia Finkler and Holloway reported a phase III trial using weekly Topotecan in recurrent endometrial cancer 23 of patients had partial response to therapy with a decrease in grade 4 neutropenia and thrombocytopenia compared to the 5-day infusion In a pilot study examining the role of 5-day Topotecan in uterine papillary serous carcinoma UPSC Chambers et al report 11 of 12 patients who received Topotecan as front-line therapy to be disease-free at 13 months median follow-up Anemia and neutropenia were managed effectively with hematopoietic stimulating factors
Taxanes have also been reported to be effective in the treatment of advanced and recurrent endometrial cancer Endometrial cancer cell lines have demonstrated sensitivity to paclitaxel Response rates of 35-37 have been reported in two separate phase II trials Günthert et al reported a complete response to Taxotere in a patient with recurrent endometrial cancer
Taxotere is an agent well documented in the management of advanced ovarian cancer with a response rate of approximately 30 in platinum-refractory patients Taxotere has also demonstrated clinical response in patients classified as paclitaxel-refractory confirming an incomplete cross-resistance between these two agents Based on these data there is reason to believe that the combination of Topotecan and Taxotere in the second-line setting may prove promising in patients initially treated with paclitaxel and platinum-based therapy
Topotecan and Taxotere have known activity in ovarian cancer patients Recent weekly dosing schedules suggest similar activity in ovarian cancer patients with less toxicity Ovarian cancer patients who have significant Taxane-related side effects including neuropathy do well with weekly Taxotere Both Topotecan and Taxotere have documented efficacy in recurrent endometrial cancer but no study to date has utilized them in combination for the treatment of endometrial cancer In addition to utilizing this regimen in a phase II setting for recurrent ovarian cancer we propose a phase II trial utilizing this combination for the treatment of recurrent endometrial cancer The justification for including all of these tumor types in the same protocol is the known similar response rates of these Gynecologic tumors to all chemotherapies The endpoints and power are designed for all of the histologic types but subset analysis will be used for each tumor type after completion of the trial
Because of the broad spectrum of antitumor activity of both Topotecan and Taxotere several phase III trials have been conducted with this combination regimen Lu and colleagues at MD Anderson administered docetaxel Taxotere intravenously on Day 1 followed by bolus daily intravenous Topotecan on days 1-3 with subcutaneous Neupogen Filgrastim support on days 4-13 Dose limiting toxicity for the regimen was febrile neutropenia and the recommended dose for phase II trials was docetaxel 75 mgm2 IV on day 1 and topotecan 14 mgm2 IV on days 1-3 with Neupogen filgrastim 5 mcgkgd SC on days 4-13 Three of the 11 patients enrolled experienced a response with the combination 1 CR and 1 PR in nasopharynx cancer and 1 PR in SCLC Aijaz and colleagues at New York Medical Center conducted a similar pilot study in patients with recurrent ovarian and primary peritoneal cancer In this trial all of the patients received docetaxel 80 mgm2 IV on day 1 and topotecan 10 mgm2 IV on days 1-5 The patients also received Neupogen filgrastim 10-mcgkg beginning on day 6 and continuing until the neutrophil count recovered to 10000mL The regimen was relatively well tolerated with neutropenia being the most frequently reported side effect Preliminary antitumor activity was impressive with 1 complete response 4 partial responses and 4 stable diseases reported among the twelve patients enrolled in the pilot study A final phase I study combining topotecan and docetaxel was also conducted at The University of Wisconsin by Stella and colleagues In this trial docetaxel was administered IV on day 1 followed by daily IV bolus Topotecan on days 1-5 In contrast to the previous studies prophylactic growth factor support was not administered following chemotherapy administration Because of significant myelosuppression at the initial dose level the protocol was amended and the starting dose of Topotecan was reduced As expected the dose-limiting toxicity was myelosuppression consisting of both neutropenia and thrombocytopenia The maximum tolerated dose for the combination regimen was docetaxel 60 mgm2 IV on day 1 followed by Topotecan 075 mgm2d on days 1-5
Recently the combination of Topotecan and Taxotere has been used in a Phase I setting in platinum sensitive patients with recurrent ovarian and primary peritoneal cancers Eleven patients have been treated to date with weekly docetaxel 30 mgm2wk plus topotecan 35 mgm2wk Two patients were non-evaluable one due to rapidly progressive disease and one due to noncompliance Of the nine evaluable patients five patients experienced dose-limiting toxicities as follows
1 cycle 1 day 15 C1D15 held due to platelets 33K in a heavily pretreated patient including previous oxaliplatin
2 C1D15 dose decreased due to grade 3 diarrhea
3 C1D8 held due to grade 3-4 nausea and vomiting may have been disease related
4 C1D15 held due to platelets 49 K 74 yo heavily pretreated including previous XRT
5 C1D15 held due to platelets 43K and declining creatinine clearance of 43 mlmin 3 prior regimens including XRT PS 2 and history of thrombocytopenia
One additional patient is planned to complete this dose level to provide 10 evaluable patients Of the 36 patients receiving 76 cycles of therapy myelosuppression was brief and reversible with no febrile neutropenia Per verbal communication from Dr Burris the recommended phase II dose will be docetaxel 30 mgm2wk plus topotecan 35 mgm2wk on days 1 8 and 15 every 28 days for minimally pretreated patients
In addition to possible synergy with this combination of drugs in other tumor types the weekly dosing may have a better safety profile The dose-limiting toxicity for Topotecan when administered on a daily x 5-administration schedule is myelosuppression However when the drug is administered on a weekly administration schedule the myelosuppression is ameliorated and is no longer dose limiting Additionally weekly docetaxel administration is gaining in popularity in the clinical arena due to the improved toxicity profile of the drug The possibility of synergy with the improved safety profile secondary to weekly dosing makes this combined dosing regimen a rational possibility for this patient population
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