Walter Sall, MD
Abramson Cancer Center of the University of Pennsylvania
Ultima Vez Modificado: 14 de noviembre del 2003
Faculty Disclosure: Howard A. Burris, III, MDbr>In this presentation Dr. Burris discusses the use of CT-2103 for the treatment of lung cancer which has not been approved by the FDA.
Presenter: Howard A. Burris, III, MD
Affiliation: Sarah Cannon Cancer Center, Nashville, Tennessee
CT-2103 (Xyotax, polyglutamated paclitaxel) has many potential advantages over other taxanes: enhanced water solubility, increased tumor penetration and serum half-life, decreased toxicity and ability to bypass MDR pumps via pinocytosis. It is conveniently administered in a 10 minute infusion without need for pre-medication and has a low incidence of alopecia and neutropenia. In vivo murine studies have confirmed the favorable pharmacokinetic profile described above. Murine tumor models have shown inproved tumor response to single agent xyotax vs. standard paclitaxel or docetaxel.
Single agent CT-2103 has been evaluated in a single arm phase two trial as first line therapy for elderly, poor performance status patients with advanced NSCLC. 28 patients were treated with CT-2103, 175mg/m2 every 3 weeks. Partial response (PR) was seen in 7%, and stable disease (SD) in 57%. No alopecia or hypersensitivity was seen. One case of febrile neutropenia and 4 cases of grade III neuropathy were observed.
A phase I dose escalation trial of CT-2103 in advanced, refractory NSCLC enrolled 12 patients; 6 received 235mg/m2 and 6 received 270mg/m2. Neutropenia and neuropathy were the primary toxicities, leading to decrease of the study dose in future patients to 175mg/m2 and 210mg/m2. PR was seen in 8% and SD in 17%. Pharmacokinetic analysis confirmed that CT-2103 does not accumulate with repeated dosing despite its serum half life of 130 hours.
Two phase I trials of combination therapy are underway: CT-2103/cisplatinum (75mg/m2) in one and CT-2103/carboplatinum (AUC 6) in the other. The majority of the patients had ovarian cancer with some primary lung cancers. In both trials, the SD + PR rate is 89%. The bulk of the toxicity has been attributed to the platinum agents rather than the CT-2103.
The summary of toxicities from completed trials show grade IV neutropenia rates of 9%, 11% and 27% at doses of 175, 210 and 235mg/m2, respectively. Cumulative neurotoxicity is seen with repeated dosing.
To date, CT-2103 has been shown to be a convenient and safe taxane derivative with encouraging activity in the phase I/II setting. Preclinical data suggest the presence of radiosensitizing capability. The completion of phase III trials will shed light on the future clinical integration of CT-2103 in NSCLC management. Trials underway include single agent CT-2103 vs. docetaxel as second line therapy of NSCLC and paclitaxel/carboplatin vs. paclitaxel/CT-2103 as first line therapy for advanced NSCLC.