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1.  Impact of race and tumor subtype on second malignancy risk in women with breast cancer 
SpringerPlus  2016;5:14.
Women with breast cancer are at increased risk of second malignancy (SM). However, the impact of race and the hormone receptor (HR) status of the primary breast tumor on risk of SM are not known. The purpose of this study is to analyze the incidence of SM in women with a history of breast cancer according to race and HR status.
In the surveillance, epidemiology, and end results database, multiple primary standardized incidence ratio sessions were used to compare the incidence of SM in women with a history breast cancer to the cancer incidence in the general population. Analyses of SM by age, race, and hormone-receptor status were performed using the absolute excess risk (AER) and observed/expected (O/E) ratio.
Younger black women (under the age of 50) were at greater risk of SM with an AER = 76.03 (O/E = 2.3, 95 % CI = 12.19–2.4) compared to younger white women who had an AER = 38.59 (O/E = 1.55, 95 % CI = 1.53–1.58). Older black women (50 years and older) had at an increased risk of SM with an AER = 42.26 (O/E = 1.3, 95 % CI = 1.26–1.34) compared to older white women who had an AER = 11.56 (O/E = 1.07, 95 % CI = 1.06–1.08). Second breast malignancy is the predominant SM in both black and white women. Women with hormone-receptor (HR)-negative breast cancer had higher risk of SMs with an AER = 43.53 (O/E = 1.41, 95 % CI = 1.38– 0.145–3.31) compared to women with HR-positive disease with an AER = 21.43 (O/E = 1.17, 95 % CI = 1.16–0.1.18). In HR-negative women, younger black women had an AER = 96.46 (O/E = 2.99, 95 % CI = 2.70–3.31), younger white women had an AER = 66 (O/E = 2.25, 95 % CI = 2.13–2.36), older black women had an AER = 58.58 (O/E = 1.45, 95 % CI = 1.34–1.57), and older white women had an AER = 20.88 (O/E = 1.14, 95 % CI = 1.11–1.18).
Black breast cancer survivors and women with HR-negative breast cancer are at increased risk of SM, which deserves further evaluation to understand the biological and clinical basis for this increased risk.
PMCID: PMC4703603  PMID: 26759753
2.  A phase I dose-escalation, safety and pharmacokinetic study of the 2-methoxyestradiol analog ENMD-1198 administered orally to patients with advanced cancer 
Investigational new drugs  2010;29(2):340-346.
2-methoxyestradiol (2ME2) is an estradiol-17β metabolite with antiproliferative and antiangiogenic activities. ENMD-1198 is an analog of 2ME2 which was developed to decrease the metabolism and increase both the bioavailability and antitumor activities of the parent molecule. This first-in-human phase I study evaluated the tolerability, pharmacokinetics and preliminary evidence of activity of ENMD-1198 in advanced cancer patients.
Eligible patients received ENMD-1198 orally once daily in Part A (standard 3+3 dose escalation design), or in Part B (accelerated dose escalation design). Cycle 1 consisted of 28 days daily dosing followed by a 14-(Part A) or 7-(Part B) day observation period, then continuously in 28 day cycles thereafter.
A total of 29 patients were enrolled in 12 dose cohorts (5 to 550 mg/m2/d). The most common drug-related toxicities were Grade 1/2 fatigue (55%), nausea and vomiting (37%), and constipation (34%). Two DLTs (Grade 4 neutropenia) occurred at 550 mg/m2/day, and 425 mg/m2/d was declared the maximum tolerated dose. ENMD-1198 was absorbed rapidly with a Tmax of 1–2 h. Exposure to ENMD-1198 (Cmax and AUC0–24hr) increased linearly with dose. The mean terminal half-life was 15 h. A 3-fold accumulation was found after multiple doses. Five patients achieved stabilization of disease for at least 2 cycles, three of whom (with neuroendocrine carcinoma of pancreas, prostate cancer and ovarian cancer) demonstrated prolonged stabilization ranging from 8–24.5 cycles.
ENMD-1198 is well-tolerated with a pharmacokinetic exposure profile compatible with once daily dosing. The recommended phase II dose of ENMD-1198 is 425 mg/m2/d. Early evidence of prolonged disease stabilization in pre-treated patients suggests ENMD-1198 is worthy of additional investigation.
PMCID: PMC4331064  PMID: 20084425
ENMD-1198; Phase I; Pharmacokinetics
3.  Sunitinib combined with pemetrexed and carboplatin in patients with advanced solid malignancies—results of a phase I dose-escalation study 
Investigational New Drugs  2013;31(6):1487-1498.
Objectives The maximum tolerated dose (MTD) and overall safety of sunitinib plus pemetrexed and carboplatin was determined in patients with advanced solid malignancies. Methods In this phase I dose-escalation study, patients received oral sunitinib on a continuous daily dosing (CDD) schedule (37.5 mg/day) or Schedule 2/1 (2 weeks on treatment, 1 week off treatment; 37.5 or 50 mg/day). Pemetrexed (400–500 mg/m2 IV) and carboplatin (AUC = 5 mg·min/ml IV) were administered q3w. At the MTD for the chosen schedule, a cohort of patients with non-small cell lung cancer (NSCLC) or mesothelioma was further evaluated. Results Twenty-one patients were enrolled on Schedule 2/1 (expansion cohort included) and 3 patients on the CDD schedule. The MTD on Schedule 2/1 was sunitinib 37.5 mg/day with pemetrexed 500 mg/m2 and carboplatin AUC = 5 mg·min/ml; MTD on the CDD schedule was not established. Dose-limiting toxicities included grade 3/4 neutropenia, grade 3 thrombocytopenia, and grade 3 hand–foot syndrome. The most common grade 3/4 drug-related non-hematologic adverse events at Schedule 2/1 MTD were fatigue/asthenia and diarrhea (both n = 4). Grade 3/4 hematologic abnormalities included neutropenia (83 %) and leukopenia (83 %). Pharmacokinetic data revealed no clinically significant drug–drug interactions. Best response at the Schedule 2/1 MTD was stable disease ≥8 weeks in 3/5 evaluable patients (60 %). Conclusions With this combination, in patients with advanced solid malignancies, sunitinib MTD on Schedule 2/1 was 37.5 mg/day. Sunitinib plus pemetrexed and carboplatin were tolerable at the MTD, although sunitinib dose delays and reductions were often required due to myelosuppression.
PMCID: PMC3825543  PMID: 23963796
Solid tumors; Non-small cell lung cancer; Sunitinib; Pemetrexed; Carboplatin
4.  Phase I Pharmacologic and Biologic Study of Ramucirumab (IMC-1121B), a Fully Human Immunoglobulin G1 Monoclonal Antibody Targeting the Vascular Endothelial Growth Factor Receptor-2 
Journal of Clinical Oncology  2010;28(5):780-787.
To evaluate the safety, maximum-tolerated dose (MTD), pharmacokinetics (PKs), pharmacodynamics, and preliminary anticancer activity of ramucirumab (IMC-1121B), a fully human immunoglobulin G1 monoclonal antibody targeting the vascular endothelial growth factor receptor (VEGFR)-2.
Patients and Methods
Patients with advanced solid malignancies were treated once weekly with escalating doses of ramucirumab. Blood was sampled for PK studies throughout treatment. The effects of ramucirumab on circulating vascular endothelial growth factor-A (VEGF-A), soluble VEGFR-1 and VEGFR-2, tumor perfusion, and vascularity using dynamic contrast-enhanced magnetic resonance imaging were assessed.
Thirty-seven patients were treated with 2 to 16 mg/kg of ramucirumab. After one patient each developed dose-limiting hypertension and deep venous thrombosis at 16 mg/kg, the next lower dose (13 mg/kg) was considered the MTD. Nausea, vomiting, headache, fatigue, and proteinuria were also noted. Four (15%) of 27 patients with measurable disease had a partial response (PR), and 11 (30%) of 37 patients had either a PR or stable disease lasting at least 6 months. PKs were characterized by dose-dependent elimination and nonlinear exposure consistent with saturable clearance. Mean trough concentrations exceeded biologically relevant target levels throughout treatment at all dose levels. Serum VEGF-A increased 1.5 to 3.5 times above pretreatment values and remained in this range throughout treatment at all dose levels. Tumor perfusion and vascularity decreased in 69% of evaluable patients.
Objective antitumor activity and antiangiogenic effects were observed over a wide range of dose levels, suggesting that ramucirumab may have a favorable therapeutic index in treating malignancies amenable to VEGFR-2 inhibition.
PMCID: PMC2834394  PMID: 20048182

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