Selective sequencing or in silico analysis for differences in DNA fragment size can improve the detection of circulating tumor DNA.

Purpose: To study the toxicity and pharmacokinetic-pharmacodynamic profile of 17-allylamino, 17- demethoxygeldanamycin (17-AAG) and to recommend a dose for phase II trials. Patients and Methods: This was a phase I study examining a once-weekly dosing schedule of 17-AAG. Thirty patients with advanced malignancies were treated. Results: The highest dose level reached was 450 mg/m²/week. The dose-limiting toxicities (DLTs) encountered were grade 3 diarrhea in three patients (one at 320 mg/m²/week and two at 450 mg/m²/week) and grade 3 to 4 hepatotoxicity (AST/ALT) in one patient at 450 mg/m²/week. Two of nine DLTs were at the highest dose level. Two patients with metastatic melanoma had stable disease and were treated for 15 and 41 months, respectively. The dose versus area under the curve-relationship for 17-AAG was linear (r² = .71) over the dose range 10 to 450 mg/m²/week, with peak plasma concentrations of 8,998 μg/L (standard deviation, 2,881) at the highest dose level. After the demonstration of pharmacodynamic changes in peripheral blood leukocytes, pre- and 24 hours post-treatment, tumor biopsies were performed and demonstrated target inhibition (c-RAF-1 inhibition in four of six patients, CDK4 depletion in eight of nine patients and HSP70 induction in eight of nine patients) at the dose levels 320 and 450 mg/m²/week. It was not possible to reproducibly demonstrate these changes in biopsies taken 5 days after treatment. Conclusion: It has been possible to demonstrate that 17-AAG exhibits a tolerable toxicity profile with therapeutic plasma concentrations and target inhibition for 24 hours after treatment and some indications of clinical activity at the dose level 450 mg/m²/week. We recommend this dose for phase II clinical trials.

Discovery of activating mutations in EGFR and their use as predictive biomarkers to tailor patient therapy with EGFR tyrosine kinase inhibitors (TKIs) has revolutionised treatment of patients with advanced EGFR-mutant non-small-cell lung cancer (NSCLC). At present, first-line treatment with EGFR TKIs (gefitinib, erlotinib, and afatinib) has been approved for patients harbouring exon 19 deletions or exon 21 (Leu858Arg) substitution EGFR mutations. These agents improve response rates, time to progression, and overall survival. Unfortunately, patients develop resistance, limiting patient benefit and posing a challenge to oncologists. Optimum treatment after progression is not clearly defined. A more detailed understanding of the biology of EGFR-mutant NSCLC and the mechanisms of resistance to targeted therapy mean that an era of treatment approaches based on rationally developed drugs or therapeutic strategies has begun. Combination approaches-eg, dual EGFR blockade-to overcome resistance have been trialled and seem to be promising but are potentially limited by toxicity. Third-generation EGFR-mutant-selective TKIs, such as AZD9291 or rociletininb, which target Thr790Met-mutant tumours, the most common mechanism of EGFR TKI resistance, have entered clinical trials, and exciting, albeit preliminary, efficacy data have been reported. In this Review, we summarise the scientific literature and evidence on therapy options after EGFR TKI treatment for patients with NSCLC, aiming to provide a guide to oncologists, and consider how to maximise therapeutic advances in outcomes in this rapidly advancing area.

Purpose: To assess the safety and tolerability, pharmacokinetics, and early evidence of antitumor activity of escalating doses of lexatumumab (HGS-ETR2), a fully human agonistic monoclonal antibody which targets and activates the tumor necrosis factor–related apoptosis-inducing ligand receptor 2 (TRAIL-R2) in patients with advanced solid malignancies. Experimental Design: In this phase 1, open label study, patients with advanced solid malignancies were treated with escalating doses of lexatumumab administered i.v. over 30 to 120 min every 21 days. A cohort of four patients, which could be expanded to six patients, was studied at each dose level. The dose-limiting toxicity (DLT) dose was defined as the dose at which the incidence of DLT in the first two cycles was ≥33%. The maximum tolerated dose was defined as the highest dose at which 10% of tumor cells for 16 of the 20 evaluable specimens submitted (80%). Conclusions: Lexatumumab was safe and well tolerated at doses up to and including 10 mg/kg every 21 days. Lexatumumab was associated with sustained stable disease in several patients. Pharmacokinetics were linear over the dose range studied, and consistent with a two-compartment model with first-order elimination from the central compartment. Additional evaluation of this novel apoptosis-inducing agent, particularly in combination with chemotherapy agents, is warranted and ongoing.

Purpose: A phase I study to define toxicity and recommend a phase II dose of the HSP90 inhibitor alvespimycin (17-DMAG; 17-dimethylaminoethylamino-17-demethoxygeldanamycin). Secondary endpoints included evaluation of pharmacokinetic profile, tumor response, and definition of a biologically effective dose (BED). Patients and Methods: Patients with advanced solid cancers were treated with weekly, intravenous (i.v.) 17-DMAG. An accelerated titration dose escalation design was used. The maximum tolerated dose (MTD) was the highest dose at which ≤1/6 patients experienced dose limiting toxicity (DLT). Dose de-escalation from the MTD was planned with mandatory, sequential tumor biopsies to determine a BED. Pharmacokinetic and pharmacodynamic assays were validated prior to patient accrual. Results: Twenty-five patients received 17-DMAG (range 2.5–106 mg/m²). At 106 mg/m² of 17-DMAG 2/4 patients experienced DLT, including one treatment-related death. No DLT occurred at 80 mg/m². Common adverse events were gastrointestinal, liver function changes, and ocular. Area under the curve and mean peak concentration increased proportionally with 17-DMAG doses 80 mg/m² or less. In peripheral blood mononuclear cells significant (P < 0.05) HSP72 induction was detected (≥20 mg/m²) and sustained for 96 hours (≥40 mg/m²). Plasma HSP72 levels were greatest in the two patients who experienced DLT. At 80 mg/m² client protein (CDK4, LCK) depletion was detected and tumor samples from 3 of 5 patients confirmed HSP90 inhibition. Clinical activity included complete response (castration refractory prostate cancer, CRPC 124 weeks), partial response (melanoma, 159 weeks), and stable disease (chondrosarcoma, CRPC, and renal cancer for 28, 59, and 76 weeks, respectively). Couclusions: The recommended phase II dose of 17-DMAG is 80 mg/m² weekly i.v. Clin Cancer Res; 17(6); 1561–70. ©2011 AACR.