Paclitaxel. (a) Topological structure of PTX. (b) 3-D conformation of PTX as observed in β-tubulin (i.e. T-Taxol). This conformer is one of the many possible options for PTX binding to MD-2 as revealed by Glide docking. MD-2 belongs to a family of proteins which express an ML (MD-2-related lipid-recognition) domain. [31] The protein contains 150 amino acids which form a “clamshell” binding site (Figure 2.2) for hydrophobic ligands inserted between two β-pleated sheets. [31, 32] These proteins include MD-1 associated with RP105 on B cells; the dust mite antigens, Der p2[33] and Der f2; [34] Xxxxxxx-Pick disease C2 (NPC2); [35] and the GM2-activating protein important in Tay-Sachs gangliosidosis. [36, 37] Der p2 exhibits the most homology to MD-2, and its NMR-determined solution structure includes a β-folded binding pocket for an unidentified lipid ligand. [32, 34] MD-2 is thus predicted to directly interact with the lipid A of endotoxin. Several important crystal structures have been published recently (human MD-2 bound to the TLR4 antagonist, lipid Iva;[38] the hiuman TLR4-MD-2 complex associated with the endotoxin antagonist eritoran; and mouse MD-2 complexed to mouse TLR4[39]). These enhance our understanding of the structure of MD-2 greatly, while offering an opportunity to explore the interaction between MD-2 and various TLR4 agonists and antagonists.
Paclitaxel. Label warnings, manufacturer’s recommendations and standard clinical practice should be followed. Guidelines for dose interruptions and dose modifications are described in Table 11. Table 11: Paclitaxel Dose Modification Guidelines Severity Grade (CTCAE v5.0 Grade) Dose Modification Hematological Toxicities Grade 1 No action Grade 2 & 3 Hold Pac until ANC and PLT levels meet the following criteria: Day 1: ANC ≥ 1.5 x 109/L (1,500/μL) and platelets ≥ 100 x 109/L (100,000/μL) Day 8, 15 & 22: ANC ≥ 1.0 x 109/L (1,000/μL) and platelets ≥ 100 x 109/L (100,000/μL) Resume treatment at same dose level Grade 4 Hold Pac until ANC and PLT levels meet the following criteria: Day 1: ANC ≥ 1.5 x 109/L (1,500/μL) and platelets ≥ 100 x 109/L (100,000/μL) Day 8, 15 & 22: ANC ≥ 1.0 x 109/L (1,000/μL) and platelets ≥ 100 x 109/L (100,000/μL) Dose reduce by 1 level and/or omit D22 dose For febrile neutropenia and/or severe bleeding, permanently discontinue Pac Non-hematological Toxicities Grade 1 No action Grade 2 No action; for patients experiencing neurotoxicity, dose reduce by 1 level and/or omit D22 dose. Grade 3 Dose reduce by 1 level and/or omit D22 dose. Grades 3 and 4 Hold Pac until the event resolves or improves to Grade 1. Dose reduce by 1 level and/or omit D22 dose. Abbreviations: ANC = absolute neutrophil count; CTCAE = common terminology criteria for adverse events; D = day; Pac = paclitaxel; PLT = platelet. Administration of granulocyte colony stimulating factor (G-CSF) or erythropoietin (EPO) is permitted as per institutional guidelines.
Paclitaxel. Pac is a taxane that can stabilize microtubules to inhibit cell division. The drug was approved for treatment of recurrent EOC when response rates (RR) of 25% to 37% were observed in multiple Phase 2 trials testing the 3-weekly schedule (XxXxxxx 1989, Xxxxxxx 1994, Xxxxxxxx 1995). In the study by Xxxxxxx et al, a median PFS of 4.2 months and an OS of 16 months were observed. A Phase 2 trial showed that weekly dosing could lead to a 20.9% XXX in platinum- and Pac- resistant EOC patients (Gynecologic Oncology Group 2006). This alternative weekly dosing schedule for Pac was studied in many trials in refractory, persistent, or recurrent EOC patients, as reviewed by Xxxxx et al (Xxxxx 2010). A randomized Phase 3 study comparing weekly vs.
