Ignite Creation Date:
2024-05-05 @ 5:35 PM
Last Modification Date:
2024-10-26 @ 9:33 AM
Study NCT ID:
NCT00484666
Status:
WITHDRAWN
Last Update Posted:
2019-09-16
First Post:
2007-06-07
Brief Title:
Platinum-Resistant Recurrent Epithelial Ovarian Cancer
Sponsor:
Carilion Clinic
Organization:
Carilion Clinic
Study Overview
Official Title:
A Phase II Study of Weekly Docetaxel and Topotecan in Patients With Platinum-Resistant Recurrent Epithelial Ovarian Cancer
Status:
WITHDRAWN
Status Verified Date:
2019-09
Last Known Status:
None
Delayed Posting:
No
If Stopped, Why?:
PI withdrew from study protocol participation
Has Expanded Access:
False
If Expanded Access, NCT#:
N/A
Has Expanded Access, NCT# Status:
N/A
Acronym:
TopoTxt
Brief Summary:
Primary objective
To estimate the overall clinical response rate CR PR SD of weekly docetaxel and weekly topotecan in women with recurrent platinum resistant ovarian or primary peritoneal cancer
Secondary objectives
To access the safety and tolerability of this novel combination chemotherapy regimen of weekly docetaxel and weekly topotecan in women with recurrent platinum resistant ovarian or primary peritoneal cancer
To estimate the progression free survival PFS and overall survival OS for women with recurrent platinum resistant ovarian or primary peritoneal cancer treated with this weekly docetaxel and weekly topotecan
To estimate the overall clinical response rate CR PR SD of weekly docetaxel and weekly topotecan in women with recurrent platinum resistant ovarian or primary peritoneal cancer
Secondary objectives
To access the safety and tolerability of this novel combination chemotherapy regimen of weekly docetaxel and weekly topotecan in women with recurrent platinum resistant ovarian or primary peritoneal cancer
To estimate the progression free survival PFS and overall survival OS for women with recurrent platinum resistant ovarian or primary peritoneal cancer treated with this weekly docetaxel and weekly topotecan
Detailed Description:
Each year more than 28000 women are diagnosed with epithelial ovarian cancer EOC Over 70 of these women will present with advanced stage III IV disease The current treatment for newly diagnosed advanced EOC involves cytoreductive surgery followed by chemotherapy The standard chemotherapy in the primary setting is a combination of a taxane either paclitaxel or docetaxel and a platinum agent either cisplatin or carboplatin Although high initial responses are seen with these primary therapies most will recur Salvage chemotherapy thus becomes the mainstay of treatment for many patients with this disease The goals of salvage therapy are to maximize tumor response while maintaining quality of life with minimal toxicity As a consequence there are a number of agents that have been studied in this recurrent setting with significant antitumor activity Two such novel agents topotecan and docetaxel are the basis of this phase I II study
Patients can be grouped into prognostic categories based on their responses to primary therapy Those with persistent disease or recurrence within 6 months of treatment are deemed platinum resistant and those achieving a greater than 6 month progression free interval are deemed platinum sensitive This distinction is important because those that are platinum sensitive have an improved overall survival and higher response rates to salvage chemotherapy The magnitude of this response increases with an increasing progression free interval The response of these patients to reintroducing either platinum or paclitaxel has been established Thigpen et al showed a 44 overall response rateORR to paclitaxel infused over 24 hours in 16 patients with a platinum free interval of greater than or equal to 6 months Kavanagh et al demonstrated a 21 partial response rate PR to the reintroduction of carboplatin after taxane treatment in 26 patients with a 12-month platinum-free intraval following platinum-refractory ovarian cancer
Topotecan has been shown to have similar activity as paclitaxel as a second line therapy with non-cross resistance Topotecan is usually administered in a daily infusion over 30 minutes in doses of 15 mgm2d x 5 consecutive days every 21 days In an effort to decrease toxicity and maintain response rates weekly schedules of topotecan have been explored Homesley et al conducted a phase I trial with single agent weekly topotecan evaluating dosages from 15 to 6 mgm2wk The recommended phase II dosage for weekly topotecan was determined to be 4 mgm2wk Dose limiting toxicities consisted of 70 non-hematologic events in 32 of 35 evaluable patients primarily consisting of grade 1 or 2 chronic fatigue 16 and gastrointestinal nausea and vomiting 23 with the majority 80 being grade 1 in severity Dose limiting myelotoxicity and thrombocytopenia were not an issue at the weekly dosages evaluated in this trial Morris and colleagues at Wayne State University are currently studying weekly topotecan in platinum sensitive patients and have reported a 40 partial response rate with 35 having stable disease Myelotoxicity was infrequent and included grade 3 or 4 neutropenia in 11 and grade 3 anemia in 18 Nonhematologic toxicity included grade 3 fatigue in 17 of patients
Abu-Rustum et al conducted a phase I trial of weekly paclitaxel 60 -100 mgm2 over 1-hour in platinum resistant patients n 18 patients recommended phase II dose 80 mgmgwk Dose limiting toxicity was defined as two or more patients with treatment delay or grade 3 toxicity at the same dose level Treatment was delayed in 2 of 3 patients at the 100 mgm2 dose level due to ANC 1500 In addition they reviewed Memorial Sloan Ketterings previous data with weekly paclitaxel 60 to 100 mgm2wk in platinum resistant patients and found an overall response rate either documented tumor shrinkage or decrease in serum CA-125 levels of 28 ORR in 13 of 45 patients In a follow up phase II trial Markman et al reported a 25 objective response rate in 13 of 51 platinum resistant patients 4 by decreasing CA-125 and 9 by 50 reduction in tumor volume Only 1 13 of 887 dosages required a dose modification due to toxicity with weekly paclitaxel at 80 mgm2wk Weekly paclitaxel is an active second-line regimen and is generally well tolerated
In advanced platinum-refractory ovarian cancer docetaxel administered every 3 weeks has demonstrated substantial single-agent efficacy with response rates ranging from 24 to 40 and an overall survival of 8 to 104 months Neutropenia was the predominant Grade 3 4 toxicity followed by fluid retention hypersensitivity reactions and diarrhea
The combination of docetaxel and carboplatin has been studied as first-line therapy for the treatment of epithelial ovarian cancer A phase II study by Markman etal utilized docetaxel 60 mgm2 plus carboplatin AUC 6 every 3 weeks demonstrated an overall response rate of 81 The most common hematologic toxicity was Grade 4 neutropenia 64 while neutropenic fever was observed in only 6 of those patients The most common non-hematologic toxicity was a mild hypersensitivity reaction 34 that did not prevent patients from completing their planned therapy
Preliminary results have recently been reported from a randomized phase III trial comparing docetaxel 75 mgm21 hr infusion to paclitaxel 175 mgm23 hr infusion in combination with carboplatin AUC 5 as calculated by 51Cr-EDTA secretion every 3 weeks as first-line chemotherapy following surgery for Stage Ic-IV ovarian cancer Both combinations demonstrated very high overall response rates of 65 and 62 respectively and an estimated 1 year disease free survival is approximately 60 for both treatment groups With regard to toxicity the occurrence of Grade 2-4 sensory neurotoxicity was significantly increased in patients receiving paclitaxel 30 compared to docetaxel 11 p001 and accounted for the majority of toxicity related treatment withdrawal in the paclitaxel group The most common severe side effect was myelosuppression with Grade 3 or 4 neutropenia occurring in 84 of patients treated with paclitaxel and 94 of patients treated with docetaxel p001 Febrile neutropenia was noted in 10 of patients treated with docetaxel compared to 2 of patients treated with paclitaxel p001 However there was no difference in septic mortality between the two treatment arms
In order to decrease the incidence of hematological toxicity associated with docetaxel administered every three weeks clinicians have explored the use of docetaxel on a weekly schedule There have been numerous published reports examining the role of weekly docetaxel single agent and in combination chemotherapy regimens in wide range of solid tumors including breast NSCLC prostate and ovarian Weekly administration of docetaxel resulted in substantial clinical activity was well tolerated and resulted in a decreased incidence of hematologic toxicity grade 34 neutropenia and leukopenia each reported in 16 of patients grade 34 anemia and thrombocytopenia in 13 and 3 of patients respectively Acute toxicities were uncommon as was peripheral neuropathy Prolonged treatment with weekly docetaxel results in chronic toxicities including asthenia fatigue edema tearing excessive lacrimation or epiphora and nail changes Chronic toxicities have been most prominent when docetaxel has been administered on a continuous weekly basis ie without a break Toxicities appeared to be delayed in onset or avoided by providing treatment breaks The current strategy is treating weekly 2 out of 3 weeks on an every 21-day cycle or weekly 3 out of 4 weeks on an every 28-day cycle The reduced incidence of myelosuppression may enhance the feasibility and tolerability of weekly docetaxel-containing combination regimens
Burris and colleagues have enrolled 36 patients in a phase I study of weekly docetaxel 20 25 30 mgm2wk and weekly topotecan 20 30 35 to 4 mgm2wk for solid tumors The combination of weekly docetaxel 30 mgm2wk plus topotecan 3 mgm2wk on days 1 8 and 15 every 28 days resulted in no dose-limiting toxicities and no dose reductions or treatment omissions were warranted during cycle 1 of therapy Non-hematologic toxicities consisted of grade 1 and 2 nausea vomiting fatigue and weakness Dose-limiting toxicity was documented for weekly docetaxel 30 mgm2wk plus topotecan 4 mgm2wk with two patients experiencing day 15 dose omissions one patients with platelets 53 K and ANC 500 and one patient with platelets 27 K who was previously treated with oxaliplatin 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
Given the results of these data and the goal to increase response rates in platinum resistant recurrent EOC patients it would seem prudent to evaluate the safety and efficacy of weekly docetaxel 30 mgm2wk plus weekly topotecan 35 mgm2wk via a phase II trial Results of this trial will be important by expanding our current knowledge base utilizing weekly scheduling of chemotherapeutic agents in regard to toxicities and response rates in platinum resistant EOC
Patients can be grouped into prognostic categories based on their responses to primary therapy Those with persistent disease or recurrence within 6 months of treatment are deemed platinum resistant and those achieving a greater than 6 month progression free interval are deemed platinum sensitive This distinction is important because those that are platinum sensitive have an improved overall survival and higher response rates to salvage chemotherapy The magnitude of this response increases with an increasing progression free interval The response of these patients to reintroducing either platinum or paclitaxel has been established Thigpen et al showed a 44 overall response rateORR to paclitaxel infused over 24 hours in 16 patients with a platinum free interval of greater than or equal to 6 months Kavanagh et al demonstrated a 21 partial response rate PR to the reintroduction of carboplatin after taxane treatment in 26 patients with a 12-month platinum-free intraval following platinum-refractory ovarian cancer
Topotecan has been shown to have similar activity as paclitaxel as a second line therapy with non-cross resistance Topotecan is usually administered in a daily infusion over 30 minutes in doses of 15 mgm2d x 5 consecutive days every 21 days In an effort to decrease toxicity and maintain response rates weekly schedules of topotecan have been explored Homesley et al conducted a phase I trial with single agent weekly topotecan evaluating dosages from 15 to 6 mgm2wk The recommended phase II dosage for weekly topotecan was determined to be 4 mgm2wk Dose limiting toxicities consisted of 70 non-hematologic events in 32 of 35 evaluable patients primarily consisting of grade 1 or 2 chronic fatigue 16 and gastrointestinal nausea and vomiting 23 with the majority 80 being grade 1 in severity Dose limiting myelotoxicity and thrombocytopenia were not an issue at the weekly dosages evaluated in this trial Morris and colleagues at Wayne State University are currently studying weekly topotecan in platinum sensitive patients and have reported a 40 partial response rate with 35 having stable disease Myelotoxicity was infrequent and included grade 3 or 4 neutropenia in 11 and grade 3 anemia in 18 Nonhematologic toxicity included grade 3 fatigue in 17 of patients
Abu-Rustum et al conducted a phase I trial of weekly paclitaxel 60 -100 mgm2 over 1-hour in platinum resistant patients n 18 patients recommended phase II dose 80 mgmgwk Dose limiting toxicity was defined as two or more patients with treatment delay or grade 3 toxicity at the same dose level Treatment was delayed in 2 of 3 patients at the 100 mgm2 dose level due to ANC 1500 In addition they reviewed Memorial Sloan Ketterings previous data with weekly paclitaxel 60 to 100 mgm2wk in platinum resistant patients and found an overall response rate either documented tumor shrinkage or decrease in serum CA-125 levels of 28 ORR in 13 of 45 patients In a follow up phase II trial Markman et al reported a 25 objective response rate in 13 of 51 platinum resistant patients 4 by decreasing CA-125 and 9 by 50 reduction in tumor volume Only 1 13 of 887 dosages required a dose modification due to toxicity with weekly paclitaxel at 80 mgm2wk Weekly paclitaxel is an active second-line regimen and is generally well tolerated
In advanced platinum-refractory ovarian cancer docetaxel administered every 3 weeks has demonstrated substantial single-agent efficacy with response rates ranging from 24 to 40 and an overall survival of 8 to 104 months Neutropenia was the predominant Grade 3 4 toxicity followed by fluid retention hypersensitivity reactions and diarrhea
The combination of docetaxel and carboplatin has been studied as first-line therapy for the treatment of epithelial ovarian cancer A phase II study by Markman etal utilized docetaxel 60 mgm2 plus carboplatin AUC 6 every 3 weeks demonstrated an overall response rate of 81 The most common hematologic toxicity was Grade 4 neutropenia 64 while neutropenic fever was observed in only 6 of those patients The most common non-hematologic toxicity was a mild hypersensitivity reaction 34 that did not prevent patients from completing their planned therapy
Preliminary results have recently been reported from a randomized phase III trial comparing docetaxel 75 mgm21 hr infusion to paclitaxel 175 mgm23 hr infusion in combination with carboplatin AUC 5 as calculated by 51Cr-EDTA secretion every 3 weeks as first-line chemotherapy following surgery for Stage Ic-IV ovarian cancer Both combinations demonstrated very high overall response rates of 65 and 62 respectively and an estimated 1 year disease free survival is approximately 60 for both treatment groups With regard to toxicity the occurrence of Grade 2-4 sensory neurotoxicity was significantly increased in patients receiving paclitaxel 30 compared to docetaxel 11 p001 and accounted for the majority of toxicity related treatment withdrawal in the paclitaxel group The most common severe side effect was myelosuppression with Grade 3 or 4 neutropenia occurring in 84 of patients treated with paclitaxel and 94 of patients treated with docetaxel p001 Febrile neutropenia was noted in 10 of patients treated with docetaxel compared to 2 of patients treated with paclitaxel p001 However there was no difference in septic mortality between the two treatment arms
In order to decrease the incidence of hematological toxicity associated with docetaxel administered every three weeks clinicians have explored the use of docetaxel on a weekly schedule There have been numerous published reports examining the role of weekly docetaxel single agent and in combination chemotherapy regimens in wide range of solid tumors including breast NSCLC prostate and ovarian Weekly administration of docetaxel resulted in substantial clinical activity was well tolerated and resulted in a decreased incidence of hematologic toxicity grade 34 neutropenia and leukopenia each reported in 16 of patients grade 34 anemia and thrombocytopenia in 13 and 3 of patients respectively Acute toxicities were uncommon as was peripheral neuropathy Prolonged treatment with weekly docetaxel results in chronic toxicities including asthenia fatigue edema tearing excessive lacrimation or epiphora and nail changes Chronic toxicities have been most prominent when docetaxel has been administered on a continuous weekly basis ie without a break Toxicities appeared to be delayed in onset or avoided by providing treatment breaks The current strategy is treating weekly 2 out of 3 weeks on an every 21-day cycle or weekly 3 out of 4 weeks on an every 28-day cycle The reduced incidence of myelosuppression may enhance the feasibility and tolerability of weekly docetaxel-containing combination regimens
Burris and colleagues have enrolled 36 patients in a phase I study of weekly docetaxel 20 25 30 mgm2wk and weekly topotecan 20 30 35 to 4 mgm2wk for solid tumors The combination of weekly docetaxel 30 mgm2wk plus topotecan 3 mgm2wk on days 1 8 and 15 every 28 days resulted in no dose-limiting toxicities and no dose reductions or treatment omissions were warranted during cycle 1 of therapy Non-hematologic toxicities consisted of grade 1 and 2 nausea vomiting fatigue and weakness Dose-limiting toxicity was documented for weekly docetaxel 30 mgm2wk plus topotecan 4 mgm2wk with two patients experiencing day 15 dose omissions one patients with platelets 53 K and ANC 500 and one patient with platelets 27 K who was previously treated with oxaliplatin 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
Given the results of these data and the goal to increase response rates in platinum resistant recurrent EOC patients it would seem prudent to evaluate the safety and efficacy of weekly docetaxel 30 mgm2wk plus weekly topotecan 35 mgm2wk via a phase II trial Results of this trial will be important by expanding our current knowledge base utilizing weekly scheduling of chemotherapeutic agents in regard to toxicities and response rates in platinum resistant EOC
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