Katherine Richardson

A Randomized, Phase II, Biomarker-Selected Study Comparing Erlotinib to Erlotinib Intercalated With Chemotherapy in First-Line Therapy for Advanced Non–Small-Cell Lung Cancer

PURPOSEnErlotinib prolongs survival in patients with advanced non-small-cell lung cancer (NSCLC). We report the results of a randomized, phase II study of erlotinib alone or intercalated with chemotherapy (CT + erlotinib) in chemotherapy-naïve patients with advanced NSCLC who were positive for epidermal growth factor receptor (EGFR) protein expression and/or with high EGFR gene copy number.nnnPATIENTS AND METHODSnA total of 143 patients were randomly assigned to either erlotinib 150 mg daily orally until disease progression (PD) occurred or to chemotherapy with paclitaxel 200 mg/m(2) intravenously (IV) and carboplatin dosed by creatinine clearance (AUC 6) IV on day 1 intercalated with erlotinib 150 mg orally on days 2 through 15 every 3 weeks for four cycles followed by erlotinib 150 mg orally until PD occurred (CT + erlotinib). The primary end point was 6-month progression-free survival (PFS); secondary end points included response rate, PFS, and survival. EGFR, KRAS mutation, EGFR fluorescent in situ hybridization and immunohistochemistry, and E-cadherin and vimentin protein levels were also assessed.nnnRESULTSnSix-month PFS rates were 26% and 31% for the two arms (CT + erlotinib and erlotinib alone, respectively). Both were less than the historical control of 45% (P = .001 and P = .011, respectively). Median PFS times were 4.57 and 2.69 months, respectively. Patients with tumors harboring EGFR activating mutations fared better on erlotinib alone (median PFS, 18.2 months v 4.9 months for CT + erlotinib).nnnCONCLUSIONnThe feasibility of a multicenter biomarker-driven study was demonstrated, but neither treatment arms exceeded historical controls. This study does not support combined chemotherapy and erlotinib in first-line treatment of EGFR-selected advanced NSCLC, and the patients with tumors harboring EGFR mutations had a better outcome on erlotinib alone.

Polymerization of 2′-fluoro- and 2′-O-methyl-dNTPs by human DNA polymerase α, polymerase γ, and primase

Studies were undertaken to assess the ability of human polymerase α (pol α) and polymerase γ (pol γ) to incorporate 2′-fluoro- and 2′-O-methyldeoxynucleotides into DNA. In vitro DNA synthesis systems were used to detect incorporation and determine Km and Vmax for 2′-FdATP, 2′-FdUTP, 2′-FdCTP, 2′-FdGTP, 2′-O-MedATP, 2′-O-MedCTP, 2′-O-MedGTP, 2′-O-MedUTP, dUTP, UTP, and FIAUTP, in addition to normal deoxynucleotides. Pol α incorporated all 2′-FdNTPs except 2′-FdATP, but not 2′-O-MedNTPs. Pol γ incorporated all 2′-FdNTPs, but not 2′-O-MedNTPs. In general, 2′-fluorine substitution decreased Vmax/Km; however, the magnitude of the changes was nucleotide dependent, with dATP and dUTP being the most affected. Misinsertion frequencies for pol α and pol γ of 2′-FdNTPs compared with their normal nucleotides were: FIAUTP > 2′-FdCTP > 2′-FdGTP > 2′-FdATP (pol γ only) > 2′-FdUTP. Because kinetics of insertion of pol α can be affected by the nature of the primer, we examined the ability of pol α to polymerize 2′-fluoro- and 2′-O-MedATP and dGTP when elongating a primer synthesized by DNA primase. Under these conditions, both 2′-FdATP and 2′-FdGTP were polymerized, but 2′-O-MedATP and 2′-O-MedGTP were not. Primase alone could not readily polymerize these analogs into RNA primers. Previous studies showed that 2′-deoxy-2′-fluorocytosine (2′-FdC) is incorporated by several non-human DNA polymerases. The current studies showed that human polymerases can polymerize numerous 2′-FdNTPs but cannot polymerize 2′-O-MedNTPs.

An Evaluation of the Toxicities of 2' -Fluorouridine and 2'-Fluorocytidine-HCI in F344 Rats and Woodchucks (Marmota monax)

The toxicities of 2-fluorouridine (2-FU) and 2-fluorocytidine-HCl (2-FC) were separately evaluated in 2 species, male Fischer 344 (F334) rats and woodchucks. Particular attention was focused on the ability of these nucleosides to induce toxicities similar to those induced by the antiviral drug fialuridine (FIAU). 2-FU or 2-FC was administered to F344 male rats by intravenous injection at doses of 5, 50, and 500 mg/kg/day for 90 consecutive days and to male and female woodchucks at doses of 0.75 and 7.5 mg/kg/ day for 90 consecutive days. Clinical chemistry, hematology, and urinalysis (woodchuck only) profiles were assessed during and at the termination of the study. At necropsy, organs were weighed and tissues collected for routine histologic analysis. Cytochrome c oxidase activity, citrate synthase activity, and mitochondrial DNA content were measured, and micronucleus formation in the bone marrow (rats only) was evaluated. No adverse clinical effects were observed in either species. Rats treated with high doses of either 2-FU or 2-FC had body weights that were 90% of those of controls. 2-FU and 2-FC both induced a moderate decrease in the median lymphocyte count, and 2-FC and 2-FU induced a mild increase in mean corpuscular hemoglobin and mean corpuscular volume. Both compounds caused slight to moderate, reversible, histologic changes in the spleen and thymus. In the woodchuck, 2-FC caused a slight increase in mean absolute lymphocytes, and 2-FC and 2-FU slightly increased hepatic periportal vacuolation and/ or mononuclear cell infiltration. In summary, neither compound showed evidence of the toxicity induced by fialuridine in either species. Although compound effects were observed, none of these effects were considered to be adverse, and the no-observed adverse effect level was determined to be 500 mg/kg/day for both compounds in the male F344 rat and 7.5 mg/kg/day in the woodchuck.