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Background: Broadly neutralizing antibodies (bnAbs) are a promising approach for HIV-1 prevention. VRC07-523LS targets the CD4-binding site of Env and was engineered for increased breadth and half-life. In the only bnAb HIV prevention efficacy studies, the AMP studies, another CD4-binding site targeting bnAb, VRC01, was administered intravenously (IV). However, subcutaneous (SC) or intramuscular (IM) administration may be preferred. We present the first interim data comparing these routes of bnAb administration from the ongoing HVTN127/HPTN087 study. Methods: 124 healthy, HIV-uninfected participants were randomized to receive VRC07-523LS via the IV (2.5 mg/kg, 5 mg/kg, 20 mg/kg), SC (2.5 mg/kg, 5 mg/kg) or IM (2.5 mg/kg, placebo) routes. Safety data were collected for 112 weeks following the first administration. VRC07-523LS serum concentrations were measured by ELISA at Day 0, 3, 6, 28, 56, 84, and 112. The log-linear portion of the time-concentration curve was used to estimate the elimination half-life. Results: Injections were well-tolerated, with mild pain or tenderness reported commonly in the SC and IM groups and mild to moderate erythema or induration reported commonly in the SC groups. Infusions were generally well-tolerated, with infusion reactions reported in 3 participants in the 20 mg/kg IV group. VRC07-523LS has an estimated median half-life of ~40 days. Median peak concentrations (with interquartile range) were 42.2 (35.1, 52.7) [mu]g/mL, 80.3 (72.3, 106.1) [mu]g/mL, and 353.6 (278.0, 461.97) [micro]g/mL for the IV groups; 11.4 (8.4, 15.2) [micro]g/mL and 24.5 (18.8, 27.0) [micro]g/mL for the SC groups; and 17.8 (15.5, 19.1) [micro]g/mL for the IM group. Geometric mean trough concentrations were 3.4 (2.5, 4.6) [micro]g/mL, 6.5 (5.6, 7.5) [micro]g/mL, and 27.2 (23.9, 31.0) [micro]g/mL for the IV groups; 0.9 (0.6, 1.4) [micro]g/mL and 3.1 (2.2, 4.3) [micro]g/mL for the SC groups; and 2.6 (2.1, 3.3) [micro]g/mL for the IM group. The peak VRC07-523LS serum concentrations increased linearly with the administered dose. At a given dose, peak and trough concentrations were highest in the IV groups and lowest in the SC groups. Conclusions: VRC07-523LS appears to be safe and well-tolerated across a range of doses and routes and is a promising bnAb for inclusion in HIV-1 prevention regimens., OA03.01 S. Walsh (1); C. Gay (2); S. Karuna (3); O. Hyrien (3); T. Skalland (3); K.H. Mayer (4); M. Sobieszczyk (5); P. Andrew (6); C. Karg (3); J. Baumblatt [...]

Background: QT prolongation is an incomplete measure of drug-induced changes in repolarization. In this study, we investigated a novel, automatic ECG technique for describing ventricular repolarization morphology and we compared these results to corrected QT (QTc) prolongation for identifying ECGs of healthy individuals on moxifloxacin.Methods: We analysed data from the US FDA ECG Warehouse involving 160 standard ECGs from 40 healthy subjects enrolled in a randomized, parallel, placebo-controlled, 'thorough QT' study. Computerized ECG analysis included a series of scalar and vectorial parameters describing duration of repolarization segments and T-wave/loop morphology including its symmetry, amplitude and shape. Binary logistic models for the identification of moxifloxacin-induced abnormalities of the repolarization were developed.Results: Moxifloxacin induced significant changes in several ECG parameters including QT and QT apex and early repolarization duration (ERD)(30)(%), T-wave amplitude and slopes of the ascending and descending arm of the T-wave. The logistic model based only on T-wave morphology parameters outperformed the model based on QTc interval for identifying the presence of moxifloxacin. Combining information about repolarization interval duration with T-wave morphology significantly improved the detection of presence of moxifloxacin (p < 0.01). The increased sensitivity of our novel ECG method contributes to a >40% reduction in the sample size required to detect significant QTc prolongation induced by moxifloxacin.Conclusions: Repolarization morphology is significantly altered by moxifloxacin. The computerized ECG technique provides a novel method for quantifying morphological changes of repolarization segment. Our new parameters reflecting the morphology of the T-wave outperformed QTc measurements when identifying moxifloxacin-induced blockade of the outward rapid components of the delayed rectifier repolarizing potassium current (I(Kr)). These data indicate that the analysis of T-wave morphology could play a role in the assessment of drug toxicity. [ABSTRACT FROM AUTHOR]

Purpose: Local and distant failure rates remain high despite aggressive chemoradiation (CRT) treatment for Stage III non-small-cell lung cancer. We conducted preclinical studies of docetaxel's cytotoxic and radiosensitizing effects on lung cancer cell lines and designed a pilot study to target distant micrometastasis upfront with one-cycle induction chemotherapy, followed by low-dose radiosensitizing docetaxel CRT.Methods and Materials: A preclinical study was conducted in human lung cancer cell lines NCI 520 and A549. Cells were treated with two concentrations of docetaxel for 3 h and then irradiated immediately or after a 24-h delay. A clonogenic survival assay was conducted and analyzed for cytotoxic effects vs. radiosensitizing effects of docetaxel. A pilot clinical study was designed based on preclinical study findings. Twenty-two patients were enrolled with a median follow-up of 4 years. Induction chemotherapy consisted of 75 mg/m(2) of docetaxel and 75 mg/m(2) of cisplatin on Day 1 and 150 mg/m(2) of recombinant human granulocyte colony-stimulating factor on Days 2 through 10. Concurrent CRT was started 3 to 6 weeks later with twice-weekly docetaxel at 10 to 12 mg/m(2) and daily delayed radiation in 1.8-Gy fractions to 64.5 Gy for gross disease.Results: The preclinical study showed potent cytotoxic effects of docetaxel and subadditive radiosensitizing effects. Delaying radiation resulted in more cancer cell death. The pilot clinical study resulted in a median survival of 32.6 months for the entire cohort, with 3- and 5-year survival rates of 50% and 19%, respectively, and a distant metastasis-free survival rate of 61% for both 3 and 5 years. A pattern-of-failure analysis showed 75% chest failures and 36% all-distant failures. Therapy was well tolerated with Grade 3 esophagitis observed in 23% of patients.Conclusions: One-cycle full-dose docetaxel/cisplatin induction chemotherapy with recombinant human granulocyte colony-stimulating factor followed by pulsed low-dose docetaxel CRT is promising with regard to its antitumor activity, low rates of distant failure, and low toxicity, suggesting that this regimen deserves further investigation. [ABSTRACT FROM AUTHOR]