Phase III trial comparing paclitaxel poliglumex vs docetaxel in the second-line treatment of non-small-cell lung cancer

Abstract

Paclitaxel poliglumex (PPX), a macromolecule drug conjugate linking paclitaxel to polyglutamic acid, reduces systemic exposure to peak concentrations of free paclitaxel. Patients with non-small-cell lung cancer (NSCLC) who had received one prior platinum-based chemotherapy received 175 or 210 mg m À2 PPX or 75 mg m À2 docetaxel. The study enrolled 849 previously treated NSCLC patients with advanced disease. Median survival (6.9 months in both arms, hazard ratio ¼ 1.09, P ¼ 0.257), 1-year survival (PPX ¼ 25%, docetaxel ¼ 29%, P ¼ 0.134), and time to progression (PPX ¼ 2 months, docetaxel ¼ 2.6 months, P ¼ 0.075) were similar between treatment arms. Paclitaxel poliglumex was associated with significantly less grade 3 or 4 neutropenia (Po0.001) and febrile neutropenia (P ¼ 0.006). Grade 3 or 4 neuropathy (Po0.001) was more common in the PPX arm. Patients receiving PPX had less alopecia and did not receive routine premedications. More patients discontinued due to adverse events in the PPX arm compared to the docetaxel arm (34 vs 16%, Po0.001). Paclitaxel poliglumex and docetaxel produced similar survival results but had different toxicity profiles. Compared with docetaxel, PPX had less febrile neutropenia and less alopecia, shorter infusion times, and elimination of routine use of medications to prevent hypersensitivity reactions. Paclitaxel poliglumex at a dose of 210 mg m À2 resulted in increased neurotoxicity compared with docetaxel. (Jemal et al, 2007). For patients who present with advanced-stage disease (IIIb or IV), platinum-based multi-agent chemotherapy modestly improves survival compared with best supportive care or singleagent therapy (Pfister et al, 2004). However, nearly all patients relapse, and only 10 -20% survive 2 years. Three agents are currently approved for second-line therapy in advanced nonsmall-cell lung cancer (NSCLC). Docetaxel and erlotinib were approved on the basis of improved survival compared with best supportive care (Shepherd et al, 2000(Shepherd et al, , 2005. Pemetrexed received approval as second-line therapy due to its similarity in survival and response rates with lower toxicity than that of docetaxel, although statistical noninferiority was not achieved (Hanna et al, 2004). Despite response rates of approximately 10%, second-line treatment improves survival by approximately 2 months compared with best supportive care.Owing to the palliative nature of second-line therapy in NSCLC and its relatively modest effect on survival, minimising the toxicity of therapy is an important consideration. Additional effective therapies that achieve that goal are needed.Paclitaxel poliglumex (PPX) is a macromolecular polymer -drug conjugate that links paclitaxel to a biodegradable polymeric backbone consisting of L-glutamic acid residues. Because the conjugation site is through the 2 0 hydroxyl of paclitaxel, a site crucial for tubulin binding, conjugated paclitaxel does not interact with b-tubulin and is biologically inactive . Paclitaxel poliglumex is relatively stable in circulation; the ar...

Self-assembled amphotericin B-loaded polyglutamic acid nanoparticles: preparation, characterization and in vitro potential against Candida albicans

“…26,27,57 For example, PGA has been used in clinical trials in the form of a covalently bound conjugate with paclitaxel (Opaxio, Cell Therapeutics, Seattle, WA, USA). 29,30 The low aqueous solubility of amphiphilic AmB (1 µg/mL) 58 makes it a suitable candidate for association with an amphiphilic PGA homopolymer. The initial reaction of AmB with PGA was carried out in the presence of dimethyl sulfoxide, a water-miscible organic solvent.…”

“…26,27 PGA has also been extensively evaluated in cancer chemotherapy and been implied at various stages of clinical trials. [28][29][30] Moreover, the development of PGA based nanoparticles involves simple and easy preparation protocol, making it a superb strategy for the encapsulation of AmB. AmB-bearing PGA nanoparticles prepared in-house were investigated for their physical characteristics, stability, safety (both in vitro and in vivo), and in vitro antifungal efficacy in comparison with two commonly used formula tions of AmB, ie, AmBisome and Fungizone.…”

Gemcitabine Plus Paclitaxel as Second-line Chemotherapy in Patients with Advanced Non-Small Cell Lung Cancer

“…Treatment-related death wasn't observed. Non-hemathologic toxicities are summarized in Table that median OS 17 weeks to 10 months, RR 0-38% (Hainsworth et al, 1995;Androulakis et al, 1998;Socinski et al, 1999;Bonomi et al, 2005;Coskun et al, 2008;Paz-Ares et al, 2008).…”

“…Platinum combination regimens with gemcitabine have resulted in response rates between 28% and 54% and 1-year survival rates between 35% and 61%, with manageable toxicity (Crino et al, 1997). Paclitaxel produces single-agent response rates between 20% and 42%, with 1-year survival rates of aproximately 40% in advanced NSCLC (Gatzemeier et al, 1995;Hainsworth et al, 1995;Bonomi et al, 2005;Paz-Ares et al, 2008). Gemcitabine and paclitaxel have shown independent activity in advanced NSCLC, lack overlapping toxic effects, and have different mechanisms of action.…”

Prognostic Significance of Telomerase Polymorphism in Non–Small Cell Lung Cancer

“…Approximately 85% of lung cancer patients have a histologic diagnosis of non-small cell lung cancer (NSCLC). Due to the delay in clinical diagnosis, only a relatively small proportion of patients (20-25%) have a resectable disease at presentation and the 5-year estimated survival rates are disappointing (2)(3)(4). Therapeutic failure and the side effects of anticancer therapy remain very important issues for future research (5).…”