Browsing by Author "Johnston, Erica L."

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    Abemaciclib in Combination with Single-Agent Options in Patients with Stage IV Non–Small Cell Lung Cancer: A Phase Ib Study
    (AACR, 2018-11) Kim, Edward S.; Kelly, Karen; Paz-Ares, Luis G.; Garrido, Pilar; Jalal, Shadia; Mahadevan, Daruka; Gutierrez, Martin; Provencio, Mariano; Schaefer, Eric; Shaheen, Monte; Johnston, Erica L.; Turner, P. Kellie; Kambhampati, Siva Rama Prasad; Beckmann, Richard; Hossain, Anwar; John, William J.; Goldman, Jonathan W.; Medicine, School of Medicine
    Purpose: Abemaciclib, a dual inhibitor of cyclin-dependent kinases 4 and 6, has demonstrated preclinical activity in non–small cell lung cancer (NSCLC). A multicenter, nonrandomized, open-label phase Ib study was conducted to test safety, MTD, pharmacokinetics, and preliminary antitumor activity of abemaciclib in combination with other therapies for treatment in patients with metastatic NSCLC. Patients and Methods: An initial dose escalation phase was used to determine the MTD of twice-daily oral abemaciclib (150, 200 mg) plus pemetrexed, gemcitabine, or ramucirumab, followed by an expansion phase for each drug combination. Pemetrexed and gemcitabine were administered according to label. The abemaciclib plus ramucirumab study examined two dosing schedules. Results: The three study parts enrolled 86 patients; all received ≥1 dose of combination therapy. Across arms, the most common treatment-emergent adverse events were fatigue, diarrhea, neutropenia, decreased appetite, and nausea. The trial did not identify an abemaciclib MTD for the combination with pemetrexed or gemcitabine but did so for the combination of abemaciclib with days 1 and 8 ramucirumab (8 mg/kg). Plasma sample analysis showed that abemaciclib did not influence the pharmacokinetics of the combination agents and the combination agents did not affect abemaciclib exposure. The disease control rate was 57% for patients treated with abemaciclib–pemetrexed, 25% for abemaciclib–gemcitabine, and 54% for abemaciclib–ramucirumab. Median progression-free survival was 5.55, 1.58, and 4.83 months, respectively. Conclusions: Abemaciclib demonstrated an acceptable safety profile when dosed on a continuous twice-daily schedule in combination with pemetrexed, gemcitabine, or ramucirumab. Abemaciclib exposures remained consistent with those observed in single-agent studies.
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    Contribution of Environment and Genetics to Pancreatic Cancer Susceptibility
    (Public Library of Science, 2014-03-20) Hocevar, Barbara A.; Kamendulis, Lisa M.; Pu, Xinzhu; Perkins, Susan M.; Wang, Zheng-Yu; Johnston, Erica L.; DeWitt, John M.; Li, Lang; Loehrer, Patrick J.; Klaunig, James E.; Chiorean, E. Gabriela; Medicine, School of Medicine
    Several risk factors have been identified as potential contributors to pancreatic cancer development, including environmental and lifestyle factors, such as smoking, drinking and diet, and medical conditions such as diabetes and pancreatitis, all of which generate oxidative stress and DNA damage. Oxidative stress status can be modified by environmental factors and also by an individual's unique genetic makeup. Here we examined the contribution of environment and genetics to an individual's level of oxidative stress, DNA damage and susceptibility to pancreatic cancer in a pilot study using three groups of subjects: a newly diagnosed pancreatic cancer group, a healthy genetically-unrelated control group living with the case subject, and a healthy genetically-related control group which does not reside with the subject. Oxidative stress and DNA damage was evaluated by measuring total antioxidant capacity, direct and oxidative DNA damage by Comet assay, and malondialdehyde levels. Direct DNA damage was significantly elevated in pancreatic cancer patients (age and sex adjusted mean ± standard error: 1.00±0.05) versus both healthy unrelated and related controls (0.70±0.06, p<0.001 and 0.82±0.07, p = 0.046, respectively). Analysis of 22 selected SNPs in oxidative stress and DNA damage genes revealed that CYP2A6 L160H was associated with pancreatic cancer. In addition, DNA damage was found to be associated with TNFA −308G>A and ERCC4 R415Q polymorphisms. These results suggest that measurement of DNA damage, as well as select SNPs, may provide an important screening tool to identify individuals at risk for development of pancreatic cancer.