bluuebunny/crossref_metadata_2025_split huggingface dataset:
Prognostic factors and outcome of atypical and anaplastic meningioma with and without radiation.
Authors: Yoon Hannah , Helenowski Irene B. , Perumal Karthikeyan , Marymont MaryAnne H. , Chandler James , Bendok Bernard R. , Rosenow Joshua M. , Mehta Minesh P. 
Published: March 2020

2083 Background: We evaluated outcome and prognostic factors for high grade meningioma (G2-3) and the role of early post-operative radiotherapy (RT). Methods: From 2000 to 2010, 136 patients were diagnosed with G2-3 meningioma at Northwestern: 124 with atypical (G2) and 12 with anaplastic (G3) meningioma. All were treated with or without RT after initial or subsequent resection. The primary endpoint was progression-free survival (PFS). Results: 21 patients received adjuvant RT, and 115 did not. Median PFS for G2 with and without RT was 68 vs.89 mos. Median PFS for G3 with and without RT was not reached=nr (mean 5) vs.60 mos (mean 35). Median PFS for Simpson G1-3 with and without RT was 18 vs.96 mos. Median PFS for Simpson G4 with and without RT was nr (mean 55) vs.59 mos (mean 44). For median follow-up of 33 mos for Simpson G1-3 and 29 mos for G4, recurrence rate for Simpson G1-3 with and without RT was 40 vs.6%, and for Simpson G4 with and without RT, 9 vs.31%. 3-yr OS for G2 with and without RT was 93 vs.94%. 3-yr OS for G3 with and without RT was 80 vs.80%. In multivariate analysis, G3 histology and Simpson grade were predictive for relapse, while brain invasion, mitoses, adjuvant RT, and location of tumor were not. For those who received adjuvant RT, mean dose of external beam radiation (EBRT) in 2 patients was 58 Gy, while mean dose of stereotactic radiosurgery (SRS) in 15 patients was 15 Gy. 51% EBRT patients recurred, while 22% SRS patients recurred (p = 0.45). Median PFS with EBRT was 43 vs.51 mos for SRS (p = 0.34). Patients were maldistributed between the with and without RT arms in terms of brain invasion, extent of resection, and G3 histology. Conclusions: Patients who received RT had lower PFS compared to those who did not; survival was comparable. This may be due to inherent selection bias for patients with more aggressive disease getting adjuvant RT. Our study may be underpowered to determine the true role of RT in G2-3 meningioma. Patients with subtotal resection, Simpson G4, who received RT had fewer recurrences and higher PFS compared to those who did not. 3-yr OS was equivalent in both G2 and G3 tumors with and without RT. G3 histology and Simpson grade were predictive for relapse while brain invasion, mitoses, adjuvant RT, and location of tumor were not.
Resectable central nervous system (CNS) metastases from colorectal cancer (CRC): Patient characteristics, outcome, and molecular correlations between primary tumor and metastases.
Authors: Bellini Elisa , Airoldi Mario , Francia di Celle Paola , Mariani Sara , Ruda Roberta , Soffietti Riccardo 
Published: March 2020

2084 Background: Aim of this study is to describe clinical characteristics and outcome of CRC patients with CNS metastases undergone to surgical resection, and report preliminary data on the comparison between molecular aspects of primary tumor and metastasis. Methods: Thirty-two pts (17 males, 15 females) with a median age of 65 yrs (range 38-80 yrs) with brain metastases from colon (23 pts, 72%) or rectum (9 pts; 28% ) adenocarcinoma (G1 in 3 pts, 9%; G2 in 12 pts, 37%; G3 in 17 pts, 53%) underwent total surgical resection. Primary tumor TNM was: T2 in 1 pt (3%), T3 in 22 pts (69%) and T4 in 9 pts (28 %); no patient had N0 status , 10 pts had N1 lesions (31%) and 22 pts had N2 (69%) lesions; 25 pts were M0 (78%) while 7 (22%) were M1. Results: One patient had neurological symptoms as first manifestation of CRC; the other cases had metachronous metastases in the SNC after a median of 35.5 months (range 4-96). The CNS location was cerebellum in 15 pts (47 %), frontal lobe in 9 pts (28 %), spinal cord in 5 pts (16% ), parietal lobe in 2 pts (6%) and occipital lobe in 1 pt (3%). Perioperative mortality was 3%. Ten pts (31%) received post-operative whole-brain radiotherapy. Six patient (19%) had local recurrence. Primary cancers harbored a K-RAS mutation in 13 cases (41%) and a BRAF mutation in 1 case (3%). Preliminary data in 20 pts indicate a 100% mutation concordance between primary tumor and CNS metastases. Conclusions: Resectable CNS metastases from CRC adenocarcinoma were seen after a median of 3 yrs originating from T3-4 N1-2 M0-1 lesions. The preferential locations in the CNS were cerebellum and frontal lobe, being spinal metastases relatively frequent. The total resection was feasible with a good long-term local control ; the whole-brain irradiation given to one third of cases could have contributed to local control. Almost all pts died of extranervous metastases. There was a concordance of KRAS and BRAF mutation in primary and CNS lesions.
Phase I study of safety and pharmacokinetics (PK) of GDC-0917, an antagonist of inhibitor of apoptosis (IAP) proteins in patients (Pts) with refractory solid tumors or lymphoma.
Authors: Tolcher Anthony W. , Papadopoulos Kyriakos P. , Patnaik Amita , Fairbrother Wayne J. , Wong Harvey , Budha Nageshwar R. , Darbonne Walter C. , Peale Franklin V. , Mamounas Michael J. , Royer-Joo Stephanie , Yu Ron , Portera Chia C. , Bendell Johanna C. , Burris Howard A. , Infante Jeffrey R. 
Published: March 2020

2503 Background: GDCE0917 is a small molecule that triggers tumor cell apoptosis by selectively antagonizing IAP proteins. Preclinical studies demonstrated antitumor efficacy of GDC-0917 alone or in combination with chemotherapeutic agents. Methods: Oral GDC-0917 was given on Day (d) 1 followed by 2d off and a 2-week (w) on/ 1w off treatment (tx) schedule (21d cycle) starting d4. A modified continual reassessment method was used for dose escalation. Dose-limiting toxicity (DLT, assessed d1-24), PK, adverse events (AEs), pharmacodynamics (PD), and clinical activity were evaluated. Results: 42 pts of age 36-86 (median 60.5) were enrolled in 11 cohorts (5-600 mg) and received 1-15 cycles (median 2) of GDC-0917. One DLT, Grade (G) 3 fatigue, was observed at 450 mg. The maximum tolerated dose was not determined although plasma concentrations of preclinically defined IC90 were reached. The most frequent AEs were diarrhea, fatigue and nausea (26.2% each), vomiting (23.8%), and constipation (19%). The most frequent AEs reported as tx-related were mostly G1-2 and included fatigue and nausea (21.4% each), vomiting (14.3%), rash (11.9%) and pruritus (9.5%). AEs reported as tx-related that were ≥ G3 in > 1 pt were elevated AST and ALT (2 pts, at 450 and 600 mg). AEs reported as tx-related that resulted in tx discontinuation were G3 fatigue, G2 QTc prolongation, G2 drug hypersensitivity, G2 pneumonitis (1 pt each), and G3 pruritus/G2 rash (same pt). GDC-0917 peak concentrations were observed 2-3h post dosing. Exposure was dose-proportional with a mean plasma elimination t1/2of 4-8h and no apparent accumulation at steady state. Rapid down-modulation of cIAP1 was observed in PBMCs at all dose levels. Evaluation of tumor biopsies demonstrated decreases in cIAP1 (2 pts total, at 40 and 200 mg) and increases in activated caspase-3 and cPARP (1 pt at 200 mg). Two pts (4.8%) had a complete response (both unconfirmed, ovarian Ca and MALT lymphoma [PET]); 4 pts (9.5%) had stable disease for ≥ 3 months. Conclusions: GDC-0917 had a favorable safety, PK and PD profile in pts with advanced malignancies. These encouraging results support further clinical evaluation of this agent. Clinical trial information: NCT01226277.
A phase I study of birinapant (TL32711) combined with multiple chemotherapies evaluating tolerability and clinical activity for solid tumor patients.
Authors: Amaravadi Ravi K. , Senzer Neil N. , Martin Lainie P. , Schilder Russell J. , LoRusso Patricia , Papadopoulos Kyriakos P. , Weng David Edward , Graham Martin , Adjei Alex A. 
Published: March 2020

2504 Background: Birinapant (B) is a SMAC-mimetic that inhibits IAPs with excellent tolerability, drug exposure, target suppression and apoptotic pathway activation in clinical studies. Preclinical studies demonstrate potent anti-tumor synergy when B is combined with TNFa-inducing chemotherapies (CT). Methods: Escalating doses of B were combined with CT in a 5-arm 3+3 phase 1 study for adults (pts) with relapsed/refractory solid tumors to determine maximum tolerated dose (MTD), pharmacokinetics (PK), and efficacy to identify indications for further studies. The arms included carboplatin/paclitaxel (CP), irinotecan (I), docetaxel (D), gemcitabine (G), and liposomal doxorubicin (LD). Results: 124 pts were treated with B at doses of 2.8 to 47 mg/m2. The MTD of B for each arm was CP (47 mg/m2); I (22 mg/m2); D (47 mg/m2). The proposed G regimen could not be administered in heavily pretreated pts and B could not be evaluated for dose escalation; this arm was discontinued and no dose-limiting toxicities (DLT) occurred. LD drug shortage prevented dose escalation for B > 35mg/m2 (MTD not reached). B did not limit CT administration for CP, I, D, LD, supporting tolerable combination of B with CT. B-associated toxicity of Bell’s palsy (Grade 2) was considered a DLT and noted at higher dose levels for I, D, and LD, but not CP. This unusual reversible toxicity occurred during cycle 1 in 7 pts. Six of these pts continued therapy without recurrence. PK studies demonstrated no effect of B on CT. Except for CP, CT did not change the PK of B. CP increased plasma PK for B, possibly due to OATP1B3 transporter effects, but without increased B toxicities. 11 pts had a partial response, 61 pts had stable disease (>2 cycles, median 4.6 mo) and 37 pts had progressive disease as their best response, with clinical benefit (CR+PR+SD) of 58%. Conclusions: B can be combined with excellent tolerability with multiple CT at standard dosing. B plus CT demonstrated clinical benefit in many tumor types. Notable clinical activity occurred with I + B in pts who had failed prior I. These results support planning for further clinical studies of the I + B, and support the hypothesis for TNFa-mediated I + B synergy. Clinical trial information: NCT01188499.
Final results of the phase I trial of niraparib (MK4827), a poly(ADP)ribose polymerase (PARP) inhibitor incorporating proof of concept biomarker studies and expansion cohorts involving BRCA1/2 mutation carriers, sporadic ovarian, and castration resistant prostate cancer (CRPC).
Authors: Michie Caroline Ogilvie , Sandhu Shahneen Kaur , Schelman William R. , Molife L Rhoda , Wilding George , Omlin Aurelius Gabriel , Kansra Vikram , Brooks David G. , Martell Robert E. , Kaye Stanley B. , De Bono Johann Sebastian , Wenham Robert Michael 
Published: March 2020

2513 Background: Niraparib(N) is an oral, potent PARP1/2 inhibitor that induces synthetic lethality in BRCA1/2 deficient tumors. PARP is also implicated in transcription regulated by the androgen receptor (AR) and rearranged ETS genes; key targets in CRPC. Methods: Dose-escalation was enriched for BRCA1/2mutation carriers (BRCA-MCs). Two MTD expansion cohorts were undertaken in patients (pts) with sporadic high grade serous ovarian cancer (HGSOC) and CRPC. In CRPC pts, archival tissue and circulating tumor cells (CTC) were analyzed for PTEN deletion and ETS gene rearrangements. Results: 100 pts [ovary (49), CRPC (23), breast (12) others (16)], received N at 10 dose levels: 30mg to 400mg daily (od), continuously. Grade (G) 4 thrombocytopenia was dose limiting at 400mg od; MTD was established at 300mg od. Drug-related toxicities were G1-2 reversible anemia (48%), fatigue (42%), nausea (42%), thrombocytopenia (35%), anorexia (27%), neutropenia (24%), constipation (23%), and vomiting (20%). PKs were dose proportional with a mean elimination t1/2of 40 hours. Peripheral blood mononuclear cells had >50% PARP inhibition from 80 mg od. gH2AX foci formation, a marker of DNA damage, was seen in CTCs. Antitumor activity occurred from 60mg od with RECIST and/or CA125 partial responses (PR) in 9/20 (45%) BRCA-MC ovarian cancer pts and 2/4 (50%) BRCA-MC breast cancer pts. Platinum-sensitive vs resistant BRCA-MC HGSOC response rate was 60% vs 33% with median time for responding pts of 429 and 340 days, respectively. In sporadic HGSOC, there were 2/3 PRs in platinum-sensitive pts, and 3/20 PRs plus 4/20 stable disease (SD) >16 weeks in platinum resistant pts. In CRPC, symptomatic benefit and SD >6 months (median 9 months) was seen in 9/21 (43%) pts treated at MTD. CTC declines of >30% (median 80%; range 36%-92%) were observed in 7/10 (70%) pts with evaluable CTC counts (≥5 cells/ 7.5mL blood). Conclusions: Niraparib was well tolerated and has promising antitumor activity in BRCA-MCs, sporadic HGSOC and CRPC. Clinical trial information: NCT0074902.
Phase I/Ib study of the PARP inhibitor olaparib (O) with carboplatin (C) in BRCA1/2 mutation carriers with breast or ovarian cancer (Br/OvCa) (NCT00647062).
Authors: Lee Jung-min , Annunziata Christina M. , Hays John L. , Noonan Anne M. , Minasian Lori M. , Zujewski JoAnne , Yu Minshu , Ji Jiuping Jay , Sissung Tristan , Houston Nicole D. , Kohn Elise C. 
Published: March 2020

2514 Background: O capsules have single agent activity against Br/OvCa in BRCA1/2mut+carriers. Our goals were to define safety and explore predictive biomarkers for an OC regimen in these pts. Methods: 3x3 dose escalation optimized daily oral O (100 or 200mg q12h; DL1&2) with IV C/AUC3 on d8 and q21d, and on DL3-6, O d1-7 at 200 then 400mg q12h with C/AUC3-5 on d2. ≤ 8 OC cycles were given, followed by daily O until progression. Safety was assessed q cycle and response q2 cycles. PBMCs were collected for polymorphism analysis (PARP1; XRCC1), and serially for PAR incorporation by ELISA. Paired tumor biopsies (pre/postC1) were collected in phase Ib pts for protein microarray (RPPA) and TUNEL endpoints. Results: 45 women (37Ov/8Br) with BRCA1 (32), BRCA2 (11), 1 each BRCA1&2 and BRCApro 68% received OC. All OvCa pts previously received C (6-55mo prior, median 14). DLT was thrombocytopenia (O 200mg q12h, C/AUC3 2/5 pts). MTD was not reached on the intermittent schedule. RP2D is O 400mg q12hx14, C/AUC5 (1/6: g4 thrombocytopenia). Gr 3/4 AEs included neutropenia (42%), thrombocytopenia (20%), anemia (13%), C hypersensitivity (9%), and fatigue (7%). 7 pts discontinued C early for hypersensitivity reaction (4) or myelosuppression (3). Responses included 1 CR (BrCa, 17mo), PR in 15/34 OvCa (44%; 3-28+mo) and 6/8 BrCa (5-24+ mo), and stabilization in 14/34 OvCa (41%; 3-25+ mo) and a BrCa pt (11mo) for a clinical benefit rate of 85% OvCa, 100% BrCa. RPPA (N=10) showed high FOXO3 and NFκB1 preC1 correlated with time on study (r=0.822, p=0.0035; r=-0.832, p=0.0028, respectively). The change post-preC1 correlated with time on study for the combination of eIF4E/G, caspase 7, pPI3K, FOXO3a, p62, E-cadherin, PCNA, Bim, and Bcl2 (r=-0.855, p=0.0068). Post-preC1 TUNEL results trended to correlate with response (p=0.07). PBMC PAR concentrations and PARP1/XRCC1 polymorphisms did not correlate with response. Conclusions: O 400mg q12h x14 with C/AUC5 q21d is active and tolerable in Br/OvCa BRCAmut+ pts despite interactive marrow suppression. Exploratory translational studies indicate FOXO3 and NFkB1 may be predictive for response to therapy, requiring a prospective validation. Clinical trial information: NCT00647062.
First-in-human evaluation of CO-1686, an irreversible, selective, and potent tyrosine kinase inhibitor of EGFR T790M.
Authors: Sequist Lecia V. , Soria Jean-Charles , Gadgeel Shirish M. , Wakelee Heather A. , Camidge D. Ross , Varga Andrea , Fidias Panos , Wozniak Antoinette J. , Neal Joel W. , Doebele Robert Charles , Garon Edward B. , Jaw-Tsai Sarah S. , Stern Jennifer C. , Allen Andrew R. , Goldman Jonathan Wade 
Published: March 2020

2524 Background: Efficacy of existing EGFR tyrosine kinase inhibitors (TKIs) in NSCLC is limited by emergence of the T790M mutation in approximately 50% of patients, and significant skin rash and diarrhea, caused by wild-type (WT)-EGFR inhibition, compromises tolerability. CO-1686 is an orally active TKI that targets common activating EGFR mutations and T790M, while sparing WT-EGFR. Animal models suggest maximal efficacy when trough plasma concentrations exceed 200ng/ml. Methods: This is a first in human phase 1 (3+3) dose-finding study of oral CO-1686, administered continuously in 21-day cycles. To be eligible, patients must have EGFR-mutant NSCLC and prior therapy with an EGFR TKI. Endpoints include safety, pharmacokinetics (PK), and efficacy. All patients undergo a biopsy for genotyping before starting study drug. Results: As of 18 Jan 2013, 35 patients (18/28 (64%) T790M+; 7 pending) have been treated with CO-1686. Dosing started at 150mg QD and escalated in steps to 900mg QD, 600mg BID and 400mg TID, with a maximum tolerated dose not yet reached. A recommended phase 2 dose is expected to be reached soon. Related AEs of grade 3 or higher were hypoglycaemia (n=1) and hyperglycaemia (n=1). AEs typical of WT-EGFR inhibition (rash, diarrhea) have not been observed. Dose-proportional PK was observed; plasma half-life was 4-5 hrs and at 900mg QD Cmax=3000ng/ml but trough concentrations were < 200ng/ml. At ≥300mg BID and TID dosing, trough concentrations can exceed 200ng/ml. At 900mg QD, 2 of 3 patients showed clinical benefit after 2 cycles of CO-1686 including one with clinically-relevant tumor shrinkage (18%) and a second with stabilization of a pleural effusion that had previously required repeat thoracenteses at ~10 day intervals. At 300mg BID, one patient (Del(19)/T790M+) with PK trough concentration >200ng/ml exhibited significant tumor shrinkage (29%) after 2 cycles. Further efficacy data from BID/TID cohorts and centrally-confirmed genotypes will be presented at the meeting. Conclusions: CO-1686 offers potential for improved activity and better tolerability over current EGFR TKIs, particularly in the treatment of T790M+ disease, an area of high unmet clinical need. Clinical trial information: NCT01526928.
Phase I, dose-escalation study of the investigational drug TAK-733, an oral MEK inhibitor, in patients (pts) with advanced solid tumors.
Authors: Adjei Alex A. , LoRusso Patricia , Ribas Antoni , Sosman Jeffrey Alan , Pavlick Anna C. , Dy Grace K. , Zhou Xiaofei , Gangolli Esha A. , Walker Russell M , Kneissl Michelle , Faucette Stephanie , Neuwirth Rachel , Bozon Viviana 
Published: March 2020

2528 Background: This first-in-human study evaluated the safety, pharmacokinetics (PK), pharmacodynamics (PD), MTD, and efficacy of TAK-733 – an oral, selective, allosteric inhibitor of MEK1/2 – in pts with advanced solid tumors (NCT00948467; completed study). Methods: Eligibility: age ≥18 y; ECOG PS 0–2; evaluable tumors. Pts received escalating doses of TAK-733 QD in a modified 3+3 design for 21 d in a 28-d cycle to determine the MTD based on DLTs in cycle 1. Plasma (PK) and peripheral blood samples (PD: pERK reduction in PBMCs) were obtained pre-dose (d 1, 8, 15, 21) and post-dose (d 1, 21) in cycle1. Results: 51 pts (median age 58 y; 51% M) received escalating doses of TAK-733 (0.2–22 mg; median 2 cycles, range 1–11 [5 pts ≥6 cycles]). 4 pts had DLTs: grade 3 acneiform dermatitis, 1 each at 11.8 and 16mg; grade 3 pustular rash and grade 2 rash/stomatitis (qualifying as a DLT) at 22mg, leading to the 16 mg dose being selected as MTD. 45 pts (88%) had a drug-related AE; most frequent was acneiform dermatitis (47%). 10 pts (20%) had a grade ≥3 drug-related AE; most frequent were creatine phosphokinase increase and acneiform dermatitis (each n=3, 6%). 7 pts discontinued due to AEs. TAK-733 exhibited a moderately fast absorption with a median Tmax of 3 hr. Steady-state exposure of TAK-733 (0.2–22mg) did not increase in a dose proportional manner based on the power model analysis. The mean terminal t1/2 (11.8, 16, and 22 mg) was 43 hr. Overall mean accumulation ratio was 3.5 following QD dosing for 21 d. On d 21, Emax of blood pERK modulation was 56–99%, and time-averaged modulation over the dosing interval at steady-state was 76–98% at MTD. This range correlates well to the 76–89% for pERK modulation associated with maximal efficacy in xenograft models. 1 pt (16 mg) with melanoma (BRAF L597R) had a confirmed partial response after 4 cycles (treated for 9 cycles). 15 pts had a best response of stable disease (4–11.7 months in 6 pts). Conclusions: From preliminary data, TAK-733 appears generally well tolerated, pharmacodynamically active and shows signs of anti-tumor activity in pts with advanced solid tumors. MTD was associated with significant pERK inhibition in peripheral blood. Clinical trial information: NCT00948467.
A phase I study of ombrabulin (O) combined with bevacizumab (B) in patients with advanced solid tumors.
Authors: Ong Michael , Del Conte Gianluca , Bahleda Rastislav , Mateo Joaquin , Damian Silvia , Perotti Antonella , Lassau Nathalie , Farace Françoise , Lovosgaldeano Jimena , Tunariu Nina , Hospitel Marie , Mariani Paola , Cohen Patrick , Capri Giuseppe , Soria Jean-Charles , Gianni Luca , Molife L Rhoda , Sessa Cristiana 
Published: March 2020

2535 Background: O, a vascular-disrupting agent derived from combretastatin A4-phosphate, induces rapid tumor vascular shutdown via endothelial cell damage. Resistance to O may occur by surges in circulating endothelial progenitors (CEP) that repopulate the tumor vasculature. Experimental models suggest prolonged and synergistic antitumor activity when O is combined with VEGF-blockade, with reduction in CEP surge. This phase I study was performed to determine the maximum tolerated dose, safety, tolerability, pharmacokinetics (PK), pharmacodynamics (PD) and preliminary antitumor activity of O combined with B. Methods: Patients (pts) with advanced treatment-refractory solid tumors, ECOG PS ≤1, and adequate organ function were eligible. O (mg/m²) was administered intravenously (IV) on day (d)1 with B (mg/kg) IV on d2 in 21d cycles (C). A Bayesian model informed dose escalation steps. PK sampling, dynamic contrast-enhanced ultrasound (DCE-US) for tumor perfusion, and CEP samples were collected. Results: 39 pts (M:F 10:29; median age 51 years [range 25-75]) were treated at 12 dose levels combining O [8 to 50mg/m2] with B [5, 10, or 15mg/kg]. Ovary (16/39, 41%) and colon (4/39, 10%) were the most common primary sites. No C1 dose-limiting toxicities occurred in 37 evaluable pts. Drug-related grade 3-4 treatment emergent adverse events (AE) were hypertension (6/39, 15%), intestinal perforation (2/39, 5%), headache (1/39, 3%), myocardial infarction (1/39, 3%), and pulmonary embolism (1/39, 3%). 36 pts (14 ovarian) were evaluable for response by RECIST 1.1. Antitumor activity was observed at O 20mg/m2+ B 10mg/kg and above, with confirmed partial responses in 2/14 pts with ovarian primary (14%), CA125 responses in 2 further ovary/endometrial cancers lasting ≥ 6 months, and stable disease in 15/36 pts (42%) lasting ≥ 6 months in 3 pts. PK indicated no interactions of O+B. Analyses of CEP levels post O and paired DCE-US data are ongoing. Conclusions: The maximum administered dose (MAD) was O 50mg/m2 with B 15mg/kg, with no dose-limiting toxicities and vascular toxicity that was manageable. Promising antitumor activity was observed at doses below the MAD and warrants further evaluation. Clinical trial information: NCT01193595.