Ignite Creation Date:
2024-05-05 @ 12:07 PM
Last Modification Date:
2024-10-26 @ 9:20 AM
Study NCT ID:
NCT00252889
Status:
COMPLETED
Last Update Posted:
2009-01-27
First Post:
2005-11-11
Brief Title:
Doxil Topotecan Doublet Cancer Study
Sponsor:
Christiana Care Health Services
Organization:
Christiana Care Health Services
Study Overview
Official Title:
GSK - Doublet A Phase I Study of Pegylated Liposomal Doxorubicin Doxil and Weekly Intravenous Topotecan in Patients With Advanced Solid Tumors
Status:
COMPLETED
Status Verified Date:
2009-01
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 objective is to determine the nature and degree of the toxicity of weekly dosing of topotecan in escalating dose levels by cohorts of 3-6 patients in combination with a fixed dose of pegylated liposomal doxorubicin Doxil
The secondary objective is to determine the activity of weekly topotecan and pegylated liposomal doxorubicin in advanced solid tumors
The secondary objective is to determine the activity of weekly topotecan and pegylated liposomal doxorubicin in advanced solid tumors
Detailed Description:
Topotecan is a semisynthetic analogue of camptothecin Like its parent compound camptothecin topotecan is a specific inhibitor of topoisomerase-I Topoisomerase-I facilitates DNA replication by inducing reversible single strand breaks thereby relieving the torsional strain which occurs ahead of the moving replication fork during DNA replication Topotecan binds to the topoisomerase-I DNA complex and prevents relegation of the single strand breaks resulting in double strand DNA breaks The cytotoxic action of topotecan is proportional to the cellular level of topoisomerase-I
Doxorubicin is an anthracycline antibiotic which has a wide range of clinical activities The mechanism of cytotoxicity and the exact intracellular target remains controversial The bulk of intracellular drug is intranuclear much of which is intercalated in the DNA Although DNA intercalation has been felt to be the principle cytotoxic mechanism more recent evidence suggests inhibition of topoisomerase-II may play a more important role Additionally other cytotoxic actions including helicase inhibition have recently been noted Pegylated liposomal doxorubicin Doxil is a polyethylene glycol pegylated liposomal encapsulation of doxorubicin This results in an alteration of the pharmacokinetics in comparison to the parent compound Specifically there is a prolonged circulation time reduced clearance a smaller volume of distribution and limited uptake by the reticuloendothelial system In animals using ovarian xenografts in nude mice pegylated liposomal doxorubicin has resulted in a greater tumor to normal tissue drug uptake and an improved therapeutic index Following phase I studies Doxil has recently been studied in a phase II study of heavily pre-treated ovarian carcinoma patients with a response rate of 257 This level of activity meets or exceeds other second-line agents currently available In the recent phase II study a dose of 50 mgm2 every 3 weeks was utilized
Topotecan given as 5 daily infusions is associated with significant myelosuppression and poor patient acceptance Non hematologic toxicities are usually mild and not dose-limiting Although the 5 day schedule can be inconvenient the relative lack of acute toxicity still makes topotecan a good candidate for out-patient chemotherapy in selected patients Although the impact of bone marrow suppression can be minimized by the use of cytokines these 5 day regimens have required substantial dose reduction
In view of the bone marrow toxicity seen with topotecan and the poor patient acceptance of a five day schedule there has been interest in the development of an effective alternate treatment regimen using topotecan Results from preclinical studies suggest that repeated administration of topotecan is necessary for its activity A phase I study evaluating the safety and efficacy of weekly bolus topotecan as a second line agent in relapsed ovarian cancer resulted in a maximum tolerated dose of 5 mgm2
A phase II study in relapsed ovarian cancer supports the use of weekly topotecan at a dose of 3 - 40 mgm2week Toxicities on this weekly regime have included grade 3 or 4 neutropenia anemia thrombocytopenia fatigue and GI toxicity each occurred following less than 1 of treatments
The combination of topoisomerase-I and topoisomerase-II inhibitors is an attractive strategy for cancer chemotherapy A phase II study evaluated the combination of pegylated liposomal doxorubicin 30mgm2week with topotecan 1 mgm2 IV for 5 consecutive days given every 28 days Twelve patients with platinum resistant ovarian cancer were treated Partial response was observed in three patients and four patients had stable disease of the ten patients evaluated for response Toxicities included a higher percentage of bone marrow toxicity grade IIIIV neutropenia grade IIIIV thrombocytopenia other toxicities included alopecia and diarrhea grade IIIII The authors concluded that the combination of topotecan and pegylated liposomal doxorubicin is active in the treatment of platinum resistant ovarian cancer However myelosuppression required dose reductions in nearly half the patients
As mentioned earlier a weekly regimen of topotecan has allowed for more convenient administration over more prolonged and more complex administration schedules The current study will evaluate the tolerability of a weekly intravenous schedule of topotecan in combination with a standard dose of pegylated liposomal doxorubicin in advanced solid tumors Due to the addition of the pegylated liposomal doxorubicin to a weekly schedule of topotecan Pharmacokinetics data will also be obtained
Doxorubicin is an anthracycline antibiotic which has a wide range of clinical activities The mechanism of cytotoxicity and the exact intracellular target remains controversial The bulk of intracellular drug is intranuclear much of which is intercalated in the DNA Although DNA intercalation has been felt to be the principle cytotoxic mechanism more recent evidence suggests inhibition of topoisomerase-II may play a more important role Additionally other cytotoxic actions including helicase inhibition have recently been noted Pegylated liposomal doxorubicin Doxil is a polyethylene glycol pegylated liposomal encapsulation of doxorubicin This results in an alteration of the pharmacokinetics in comparison to the parent compound Specifically there is a prolonged circulation time reduced clearance a smaller volume of distribution and limited uptake by the reticuloendothelial system In animals using ovarian xenografts in nude mice pegylated liposomal doxorubicin has resulted in a greater tumor to normal tissue drug uptake and an improved therapeutic index Following phase I studies Doxil has recently been studied in a phase II study of heavily pre-treated ovarian carcinoma patients with a response rate of 257 This level of activity meets or exceeds other second-line agents currently available In the recent phase II study a dose of 50 mgm2 every 3 weeks was utilized
Topotecan given as 5 daily infusions is associated with significant myelosuppression and poor patient acceptance Non hematologic toxicities are usually mild and not dose-limiting Although the 5 day schedule can be inconvenient the relative lack of acute toxicity still makes topotecan a good candidate for out-patient chemotherapy in selected patients Although the impact of bone marrow suppression can be minimized by the use of cytokines these 5 day regimens have required substantial dose reduction
In view of the bone marrow toxicity seen with topotecan and the poor patient acceptance of a five day schedule there has been interest in the development of an effective alternate treatment regimen using topotecan Results from preclinical studies suggest that repeated administration of topotecan is necessary for its activity A phase I study evaluating the safety and efficacy of weekly bolus topotecan as a second line agent in relapsed ovarian cancer resulted in a maximum tolerated dose of 5 mgm2
A phase II study in relapsed ovarian cancer supports the use of weekly topotecan at a dose of 3 - 40 mgm2week Toxicities on this weekly regime have included grade 3 or 4 neutropenia anemia thrombocytopenia fatigue and GI toxicity each occurred following less than 1 of treatments
The combination of topoisomerase-I and topoisomerase-II inhibitors is an attractive strategy for cancer chemotherapy A phase II study evaluated the combination of pegylated liposomal doxorubicin 30mgm2week with topotecan 1 mgm2 IV for 5 consecutive days given every 28 days Twelve patients with platinum resistant ovarian cancer were treated Partial response was observed in three patients and four patients had stable disease of the ten patients evaluated for response Toxicities included a higher percentage of bone marrow toxicity grade IIIIV neutropenia grade IIIIV thrombocytopenia other toxicities included alopecia and diarrhea grade IIIII The authors concluded that the combination of topotecan and pegylated liposomal doxorubicin is active in the treatment of platinum resistant ovarian cancer However myelosuppression required dose reductions in nearly half the patients
As mentioned earlier a weekly regimen of topotecan has allowed for more convenient administration over more prolonged and more complex administration schedules The current study will evaluate the tolerability of a weekly intravenous schedule of topotecan in combination with a standard dose of pegylated liposomal doxorubicin in advanced solid tumors Due to the addition of the pegylated liposomal doxorubicin to a weekly schedule of topotecan Pharmacokinetics data will also be obtained
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