Citations

Abstract Purpose: First-in-human phase I trial to determine the safety, pharmacokinetics, and antitumor activity of BIND-014, a novel, tumor prostate-specific membrane antigen (PSMA)–targeted nanoparticle, containing docetaxel. Experimental Design: Patients with advanced solid tumors received BIND-014 every three weeks (n = 28) or weekly (n = 27), with dose levels ranging from 3.5 to 75 mg/m2 and 15 to 45 mg/m2, respectively. Results: BIND-014 was generally well tolerated, with no unexpected toxicities. The most common drug-related toxicities (>20% of patients) on either schedule included neutropenia, fatigue, anemia, alopecia, and diarrhea. BIND-014 demonstrated a dose-linear pharmacokinetic profile, distinct from docetaxel, with prolonged persistence of docetaxel-encapsulated circulating nanoparticles. Of the 52 patients evaluable for response, one had a complete response (cervical cancer on the every three week schedule) and five had partial responses (ampullary adenocarcinoma, non–small cell lung, and prostate cancers on the every-three-week schedule, and breast and gastroesophageal cancers on the weekly schedule). Responses were noted in both PSMA-detectable and -undetectable tumors. Conclusions: BIND-014 was generally well tolerated, with predictable and manageable toxicity and a unique pharmacokinetic profile compared with conventional docetaxel. Clinical activity was noted in multiple tumor types. The recommended phase II dose of BIND-014 is 60 mg/m2 every three weeks or 40 mg/m2 weekly. Clin Cancer Res; 22(13); 3157–63. ©2016 AACR.

Abstract Background: MRX34 is a liposome-formulated double-stranded mimic of tumor suppressor microRNA-34 (miR-34), which is lost or expressed at reduced levels in many solid and hematologic malignancies. miR-34 functions in the p53 tumor suppressor pathway and regulates the expression of more than 20 cancer-related genes including BCL2, E2F3, HDAC1, MET, MEK1, CDK4/6, PDGFR-ɑ, SIRT1, WNT1/3, NOTCH-1, β-catenin, CD44, Nanog and AXL. miR-34 also suppresses stem-like properties in cancer cells and sensitizes cancer cells to cytotoxic and targeted therapies. A multicenter phase I clinical trial of MRX34 is being conducted in patients with unresectable hepatocellular carcinoma or metastatic cancer with liver involvement. Methods: Eligible patients are enrolled in a standard 3 + 3 dose escalation study at MRX34 starting dose of 10 mg/m2, administered IV on days 1, 4, 8, 11, 15, and 18 of 28-day cycles. Dexamethasone premedication was added after the first 2 dose levels. The primary objective is to determine the RP2D, and secondary objectives include assessments of safety, PK and objective response rate (ORR). Response is evaluated by CT/MRI every 8 weeks. Once RP2D has been established, expansion cohort will be treated at the RP2D, with specific focus on determining biological response in tumor biopsy material. The latter will include assessing tumor uptake of miR-34 mimic and down-regulation of target gene expression as was observed in animal models of cancer. Results: Twenty-five patients received study drug, and enrollment is currently ongoing at the 5th dose level (70 mg/m2) and MTD has not been reached. There were 18 Caucasians, 15 males, with a median age of 62.5 years and a median of 4 prior treatments. Liposomal formulation-associated infusion reactions have been observed as characterized by the following treatment emergent adverse events (AEs) out of 20 patients: fever (13), chills (12), fatigue (12), thrombocytopenia (8), diarrhea (8), back/flank pain (6), nausea (6), and neutropenia (4). Most common Gr 3/4 AEs were neutropenia (4), thrombocytopenia (3), fatigue (2), AST/ALT elevation (4) and back/flank pain (2). Addition of pre-dose dexamethasone with higher dose levels ameliorated infusion reactions. One patient died on study from disease progression. One dose-limiting toxicity was observed at the 2nd dose level (20 mg/m2; Gr 3 acute kidney injury associated with nausea, vomiting, diarrhea and dehydration) and one at the 5th dose level (70 mg/m2; Gr 3 increased AST). Conclusions: MRX34 has a manageable safety profile in patients with unresectable primary liver cancer or metastatic cancer with liver involvement. Determination of the R2PD, assessment of clinical response, and analyses of molecular markers are ongoing. Citation Format: Muhammad Shaalan Beg, Mitesh Borad, Jasgit Sachdev, David S. Hong, Susan Smith, Andres Bader, Jay Stoudemire, Sinil Kim, Andrew Brenner. Multicenter phase I study of MRX34, a first-in-class microRNA miR-34 mimic liposomal injection. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr CT327. doi:10.1158/1538-7445.AM2014-CT327

Abstract Background: Overexpression of COX-2 has been associated with worse outcome in NSCLC. In C30203, we found that administration of the selective COX-2 inhibitor celecoxib in addition to chemotherapy in advanced NSCLC improved outcome (progression free and overall survival, PFS, OS) in pts with moderate to high COX-2 expression by immunohistochemistry (IHC). C30801 was designed to prospectively confirm that finding. Patients and Methods: Pts with NSCLC (stage IIIb with pleural effusion, IV 6th ed) were pre-registered and biopsy specimens analyzed for COX-2 by IHC. Pts with COX-2 expression > or = 2, PS 0-2 and normal organ function were eligible. Chemotherapy was determined by histology: carboplatin (AUC = 6), pemetrexed (500 mg/m2) d 1, q21 days for pts with non-squamous NSCLC; carboplatin(AUC=5.5) d1, gemcitabine (1000 mg/m2) d 1,8 for pts with squamous histology. Randomization was to celecoxib (400 mg bid) (Arm A) or placebo (Arm B). The primary endpoint was to demonstrate improvement in PFS in patients with COX-2 index >=4 with hazard ratio of 0.645. Results: The study was halted by the DSMB for futility after 312 of the planned 322 pts were randomized. The current analysis is based upon the first 300 pts. There were no significant differences between the groups (Table). There was a possible harmful effect for COX-2 inhibition in the COX-2 2-3 subset (OS HR = 1.75, p =.0977). Toxicity was similar for both arms. Subset analyses evaluating histology, chemotherapy regimen, incremental COX-2 expression did not demonstrate any advantage for COX-2 inhibition. Conclusions: 1. COX-2 expression by IHC failed to select pts who could benefit from selective COX-2 inhibition. 2. COX-2 inhibition did not significantly increase toxicity associated with chemotherapy or increase cardiovascular morbidity. 3. We will evaluate other possible determinants of toxicity and response to COX-2 inhibition. OutcomeArm AArm BCOX-2 2-3 (n=37)COX-2 > or = 4 (n=111)COX-2 2-3 (n=46)COX-2 > or = 4 (n=106)PFS (months)4.404.934.606.11OS (months)9.0310.5814.8512.68 Citation Format: Martin J. Edelman, Xiaofei Wang, Lydia Hodgson, Richard T. Cheney, Maria Baggstrom, Thomas Sachdev, Ajeet Gajra, Erin Bertino, Karen Reckamp, Julian Molina, Joan Schiller, Kisha Mitchell-Richards, Paula Friedman, Jon Ritter, Everett Vokes, Alliance for Clinical Trials in Oncology. Phase III randomized, placebo controlled trial of COX-2 inhibition in addition to standard chemotherapy for advanced non-small cell lung cancer (NSCLC):CALGB 30801 (Alliance). [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr CT238. doi:10.1158/1538-7445.AM2014-CT238

Abstract Background An international Delphi panel has defined a harmonized protocol (HarP) for the manual segmentation of the hippocampus on MR. The aim of this study is to study the concurrent validity of the HarP toward local protocols, and its major sources of variance. Methods Fourteen tracers segmented 10 Alzheimer's Disease Neuroimaging Initiative (ADNI) cases scanned at 1.5 T and 3T following local protocols, qualified for segmentation based on the HarP through a standard web‐platform and resegmented following the HarP. The five most accurate tracers followed the HarP to segment 15 ADNI cases acquired at three time points on both 1.5 T and 3T. Results The agreement among tracers was relatively low with the local protocols (absolute left/right ICC 0.44/0.43) and much higher with the HarP (absolute left/right ICC 0.88/0.89). On the larger set of 15 cases, the HarP agreement within (left/right ICC range: 0.94/0.95 to 0.99/0.99) and among tracers (left/right ICC range: 0.89/0.90) was very high. The volume variance due to different tracers was 0.9% of the total, comparing favorably to variance due to scanner manufacturer (1.2), atrophy rates (3.5), hemispheric asymmetry (3.7), field strength (4.4), and significantly smaller than the variance due to atrophy (33.5%, P < .001), and physiological variability (49.2%, P < .001). Conclusions The HarP has high measurement stability compared with local segmentation protocols, and good reproducibility within and among human tracers. Hippocampi segmented with the HarP can be used as a reference for the qualification of human tracers and automated segmentation algorithms.

Abstract There is increasing evidence that subjective cognitive decline (SCD) in individuals with unimpaired performance on cognitive tests may represent the first symptomatic manifestation of Alzheimer's disease (AD). The research on SCD in early AD, however, is limited by the absence of common standards. The working group of the Subjective Cognitive Decline Initiative (SCD‐I) addressed this deficiency by reaching consensus on terminology and on a conceptual framework for research on SCD in AD. In this publication, research criteria for SCD in pre‐mild cognitive impairment (MCI) are presented. In addition, a list of core features proposed for reporting in SCD studies is provided, which will enable comparability of research across different settings. Finally, a set of features is presented, which in accordance with current knowledge, increases the likelihood of the presence of preclinical AD in individuals with SCD. This list is referred to as SCD plus .

Background— Pulmonary arterial hypertension (PAH) is characterized by pulmonary vascular remodeling and right heart failure. The right (RV) and left ventricles (LV) do not function in isolation, sharing a common pericardial sac and interventricular septum. We sought to define the clinical and prognostic significance of ventricular interdependence in PAH and its association with LV filling patterns through speckle-tracking strain echocardiography. Methods and Results— Echocardiography was performed in 71 adults with a new diagnosis of PAH. To analyze LV and RV function separately, we measured peak systolic longitudinal and circumferential strain of the LV and RV. Survival was assessed >2 years. Patients had dilated right-sided chambers (right atrial volume index, 44±19 mL/m 2 ; RV end-diastolic area, 34±9 cm 2 ), and reduced RV function (RV fractional area change, 28±12%). Speckle-tracking echocardiography revealed significant reductions in RV free wall peak systolic strain (−15±3%). Despite normal LV size and normal conventional measures of LV systolic function (end-diastolic dimension, 42±6 mm; ejection fraction, 65±8%; cardiac index, 2.6±0.8 L/min per m 2 ), patients had reduced LV free wall systolic strain (−15±3%). Decreased LV free wall systolic strain was associated with a delayed relaxation mitral inflow Doppler pattern, P =0.0002. During 2-year follow-up, 19 patients (27%) died. LV strain was associated with increased mortality (unadjusted hazard ratio, 2.40 per 5% decrease in LV free wall strain, 1.22–4.68), which remained significant when adjusted for age, sex, World Health Organization functional class, and PAH pathogenesis (hazard ratio, 3.11, 1.38–7.20). Conclusions— The pressure loading in PAH results in geometric alterations and functional decline of the RV, with marked reduction in RV systolic strain. Despite preservation of LV ejection fraction, LV systolic strain was also reduced and associated with early mortality, highlighting the significance of ventricular interdependence in PAH.

Purpose Hand-foot syndrome (HFS) is a dose-limiting toxicity of capecitabine for which no effective preventative treatment has been definitively demonstrated. This trial was conducted on the basis of preliminary data that a urea/lactic acid–based topical keratolytic agent (ULABTKA) may prevent HFS. Patients and Methods A randomized, double-blind phase III trial evaluated 137 patients receiving their first ever cycle of capecitabine at a dose of either 2,000 or 2,500 mg/m2 per day for 14 days. Patients were randomly assigned to a ULABTKA versus a placebo cream, which was applied to the hands and feet twice per day for 21 days after the start of capecitabine. Patients completed an HFS diary (HFSD) daily. HFS toxicity grade (Common Terminology Criteria for Adverse Events [CTCAE] v3.0) was also collected at baseline and at the end of each cycle. The primary end point was the incidence of moderate/severe HFS symptoms in the first treatment cycle, based on the patient-reported HFSD. Results The percentage of patients with moderate/severe HFS symptoms was not different between groups, being 13.6% in the ULABTKA arm and 10.2% in the placebo arm (P = .768 by Fisher's exact test). The odds ratio was 1.37 (95% CI, 0.37 to 5.76). Cycle 1 CTCAE skin toxicity was higher in the ULABTKA arm but not significantly so (33% v 27%; P = .82). No significant differences were observed in other toxicities between groups. Conclusion These data do not support the efficacy of a ULABTKA cream for preventing HFS symptoms in patients receiving capecitabine.

Purpose Risedronate prevents bone loss in postmenopausal women. The purpose of this study was to determine whether risedronate prevents bone loss in premenopausal women undergoing chemotherapy for breast cancer. Patients and Methods Premenopausal women undergoing chemotherapy for breast cancer were treated with oral calcium 600 mg and vitamin D 400 U daily and randomly assigned to receive oral risedronate 35 mg weekly or placebo, with all these therapies beginning within a month of the start of chemotherapy. Most chemotherapy regimens included anthracyclines, taxanes, or cyclophosphamide. Bone mineral density (BMD) was measured at baseline and 1 year. The primary end point was the change in lumbar spine (LS) BMD from baseline to 1 year. Results A total of 216 women enrolled; 170 women provided BMD data at 1 year. There was no difference in the mean change or percent change in LS BMD between groups, with a loss of 4.3% in the risedronate arm and 5.4% for placebo at 1 year (P = .18). Loss of BMD at the femoral neck and total hip were also similar between treatment groups. Risedronate was well tolerated, with no significant differences in adverse events compared with placebo, except that arthralgias and chest pain were worse in those receiving the placebos. Conclusion Risedronate did not prevent bone loss in premenopausal women undergoing adjuvant chemotherapy for breast cancer.

Purpose A randomized three-arm phase II study was undertaken to evaluate the optimum administration schedule of pemetrexed and gemcitabine in chemotherapy-naïve patients with non–small-cell lung cancer. Patients and Methods Patients were randomly assigned to three schedules of pemetrexed 500 mg/m2 plus gemcitabine 1,250 mg/m2, separated by a 90-minute interval, on a 21-day cycle as follows: schedule A, pemetrexed followed by gemcitabine on day 1 and gemcitabine on day 8; schedule B, gemcitabine followed by pemetrexed on day 1 and gemcitabine on day 8; and schedule C, gemcitabine on day 1 and pemetrexed followed by gemcitabine on day 8. Results One hundred fifty-two eligible patients (schedule A, n = 59; schedule B, n = 31, and schedule C, n = 62) received a median of five (schedule A), two (schedule B), and four (schedule C) treatment cycles. Overall, 66% of patients experienced grade 3 or 4 neutropenia. Common grade 3 and 4 nonhematologic toxicities were dyspnea (11%), fatigue (16%), and transaminase elevation (9%). Schedule A seemed less toxic compared with schedule C (grade 3 or 4 events: 86% v 94%, respectively; P = .19; grade 4 events: 39% v 48%, respectively; P = .30). Schedule B was closed at interim analysis for inferior efficacy. Schedule A, with a confirmed response rate of 31% (95% CI, 20% to 45%), met the protocol-defined efficacy criteria, whereas schedule C, with a confirmed response rate of 16.1% (95% CI, 11% to 34%), did not. Median survival time and time to progression were 11.4 and 4.4 months, respectively, with no observable difference between the arms. Conclusion Pemetrexed and gemcitabine administered as outlined for schedule A met the protocol-defined efficacy criteria, was less toxic compared with the other treatment schedules, and should be further evaluated.