CT-2103: emerging utility and therapy for solid tumours.
Expert Opin Investig Drugs. 2004 Nov ; 13(11): 1501-8
Langer CJ.
[This is the second time in a couple of months, that Dr. Langer has had an article about Xyotax published. The first one appeared in The Oncologist ( theoncologist.alphamedpress.org ).
I must confess that I don't understand the logic behind this. Langer is evidently the principal investigator for Stellar 3. I would expect him to lie low until the results are available and only if they are positive publish these kind of reviews. Writing positive articles just before the moment of truth only to shortly thereafter having the trial fail on him will only make him look stupid. Or at least rather gullible.
Langer is clearly a person with status within the community. He has been giving oral presentations at ASCO. He is presented in Medscape as an expert on the subject (Hematology-Oncology February 2004 medscape.com ) and he has extensive ties to the industry, taking money from Bristol-Myers Squibb, Pharmacia, Lilly, Schering-Plough, Aventis, Amgen, Cell Therapeutics Inc, Ortho Biotech, Celgene, Vertex, Genentech, AstraZeneca, and Pfizer. Why not just wait a couple of months until the data has been unblinded? We are not talking about years here].
Fox Chase Cancer Center, Thoracic Oncology, Philadelphia, PA 19111, USA. CJ_Langer@fccc.edu
CT-2103 (XYOTAX, Cell Therapeutics, Inc.) is a conjugate of paclitaxel to a polyglutamate polymer. Its macromolecular nature exploits enhanced permeability and retention in tumour tissues. This compound is stable and inactive in aqueous solution and undergoes predominantly intracellular metabolism at the site where active paclitaxel is released. Because it does not require a Cremophor EL vehicle, it can be administered by short infusion into peripheral veins.
In preclinical models, compared with the same dose of unconjugated paclitaxel in Cremophor EL-ethanol, CT-2103 yields >or= 12-fold increase in area under the curve in both plasma and tumour tissue. This alteration in drug pharmacokinetics and biodistribution is attributable to the ability of macromolecules to concentrate in areas of vascular leakiness, such as tumour tissue.
CT-2103 is taken up by both tumour cells and normal phagocytic cells and is transported to lysosomes, where it is released by specific proteases through enzymatic action. In syngeneic and xenogeneic tumour models, at the maximally tolerated dose, CT-2103 appears to be more active than the standard doses of paclitaxel. It has also demonstrated activity in paclitaxel-resistant tumour models.
Its potential enhancement of efficacy and decrease in drug-related toxicities make this agent an attractive option for therapeutic investigation. In Phase I trials it has been relatively well-tolerated, with acceptable toxicity at doses <or= 225 mg/m(2) every 3 weeks. In combination with carboplatin the maximum tolerated dose is 235 mg/m(2) and the recommended Phase II dose 210 mg/m(2). Activity has been demonstrated in both non-small cell lung carcinoma (NSCLC) and in ovarian cancer,
Phase III studies are currently testing this agent versus standard paclitaxel as maintenance therapy for first-line treatment-naive ovarian cancer. In addition, CT-2103 at a dose of 210 mg/m(2) (performance status [PS] 0 - 1) or 175 mg/m(2) (PS 2) is being compared with docetaxel (75 mg/m(2)) for the second-line treatment of NSCLC. In front-line PS 2 NSCLC patients, this agent in combination with carboplatin is undergoing comparison with paclitaxel/carboplatin; in a separate effort, single-agent CT-2103 is being compared with either gemcitabine or vinorelbine. These studies will determine whether the preclinical and early clinical promise of this agent can be realised in the clinical treatment of solid tumours. |
