GSK - Doublet: A Phase I Study of Pegylated Liposomal Doxorubicin (Doxil) and Weekly Intravenous Topotecan in Patients With Advanced Solid Tumors

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 25.7%. This level of activity meets or exceeds other second-line agents currently available. In the recent phase II study, a dose of 50 mg/m2 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 mg/m2.

A phase II study in relapsed ovarian cancer supports the use of weekly topotecan at a dose of 3 - 4.0 mg/m2/week. 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.