bluuebunny/crossref_metadata_2025_split huggingface dataset:
Can estimated glomerular filtration rate (eGFR) replace isotopic measurement of GFR for carboplatin dosing in stage 1 seminoma?
Authors: Shepherd Scott T.C. , Gillen Gerry , Morrison Paula , Forte Carla , MacPherson Iain R. , Mark Patrick , White Jeff D. 
Published: March 2020

2589 Background: Accurate determination of GFR is essential for correct dosing of carboplatin, the standard adjuvant therapy for stage 1 seminoma. Isotopic methods (e.g. 51Cr-EDTA) remain the gold standard for determination of GFR. However, the use of eGFR could reduce the need for such isotope studies. As novel formulae to estimate GFR such as CKD-EPI and MDRD4 have improved the assessment of renal function in non-oncological settings, we investigated their utility for carboplatin dosing. Methods: 115 patients (pts) (mean age 40.3, std dev. 10.1) who received adjuvant carboplatin for stage 1 seminoma at our institution between 2007-2012 were identified. All pts underwent 51Cr-EDTA measurement of GFR with carboplatin dose calculated using the Calvert formula, based on GFR uncorrected for body surface area (BSA). Theoretical carboplatin doses were then calculated using eGFR values obtained using the CKD-EPI and MDRD4 formulae with additional calculation to uncorrect for BSA. Creatinine clearance was calculated by Cockcroft-Gault (CG) formula. For each pt the carboplatin doses calculated by eGFR were compared with the actual dose calculated by the gold-standard method; a difference of less than 10% was considered acceptable. Results: The Table shows the percentage of pts who would have received an equivalent carboplatin dose using each eGFR formula compared to the dose calculated using 51Cr-EDTA. The CKD-EPI formula performed best with 58.9% of pts receiving within 10% of the correct dose. Pts predicted to be underdosed by CKD-EPI eGFR were more likely to be obese (BMI >30) (p=0.01); there were no predictors of the 18.8% who would have received an excess dose. Conclusions: Our data support further evaluation of the CKD-EPI formula but highlight the clinically significant variances in carboplatin dosing when using non-isotopic methods of GFR estimation. [Table: see text]
Copper transporter CTR1 expression and tissue platinum concentration in NSCLC.
Authors: Kilari Deepak , Tang XiMing , Chow Chi-Wan , Fujimoto Junya , Kalhor Neda , Swisher Stephen , Wistuba Ignacio Ivan , Stewart David J. , Siddik Zahid Hussain , Kim Eric S. 
Published: March 2020

2601 Background: Platinum (Pt) resistance is a major limitation in the treatment of advanced non-small cell lung cancer (NSCLC). We previously demonstrated that low tissue Pt concentration in NSCLC tumor specimens was significantly associated with reduced tumor response and worse survival. Furthermore, low expression of the copper transporter CTR1, a transporter of Pt uptake is reported to be associated with poor clinical outcome following Pt-based therapy in NSCLC patients. However, a defect in CTR1expression as a causative factor in reduced Pt accumulation in NSCLC tissues is not well-established. We investigated the relationship between tissue Pt concentrations and CTR1 expression in NSCLC specimens. Methods: We identified paraffin-embedded NSCLC tissue blocks from 30 patients who underwent neoadjuvant Pt-based chemotherapy with known tissue Pt concentrations at MD Anderson Cancer Center. Expression of CTR1 was determined by immunohistochemistry with adequate controls; 0 = undetectable; 1+ = barely detectable staining; 2+ = readily appreciable staining; and 3+ = dark brown staining. Pt concentration was compared between different CTR1 expression groups. Results: Tissue Pt concentration significantly correlated with tumor response in 30 patients who received neoadjuvant Pt-based chemotherapy (P<0.001). There was an uneven distribution of CTR1 expression scores with a majority of specimens demonstrating scores of 2+ (N=15, 50%). There were 2 specimens with no detectable CTR1 expression (score of 0) and 6 patients with a score of 3+. Patients with undetectable CTR1 expression in their tumors had significantly lower Pt concentrations compared to those with scores of 3+ (P=0.014). Furthermore, those with undetectable CTR1 expression had reduced tumor response compared to those with scores of 3+ following Pt-based chemotherapy (P=0.039). Conclusions: To the best of our knowledge, this is the first study to correlate CTR1 expression in clinical specimens to both tumor Pt uptake and response. Patients with undetectable CTR1 expression in their tumors had significantly lower Pt concentration and reduced tumor response. Further evaluation with a larger sample size is required. (Supported by 2012 ASCO Young Investigator Award)
Phase I expansion trial of an oral TORC1/TORC2 inhibitor (CC-223) in advanced solid tumors.
Authors: Varga Andrea , Mita Monica M. , Wu Jennifer J. , Nemunaitis John J. , Cloughesy Timothy Francis , Mischel Paul S. , Bendell Johanna C. , Shih Kent C. , Paz-Ares Luis G. , Mahipal Amit , Delord Jean-Pierre , Kelley Robin Katie , Soria Jean-Charles , Wong Lilly , Xu Shuichan , James Angela , Wu Xiaoling , Chopra Rajesh , Hege Kristen , Munster Pamela N. 
Published: March 2020

2606 Background: CC-223 is an ATP-competitive inhibitor of the mTOR kinase, including both TORC1 and TORC2. CC-223 was selected to address resistance of rapamycin analogues mediated by TORC2 activation. Methods: Following establishment of the MTD (reported at ASCO 2012), subjects with select advanced, refractory solid tumors, including NSCLC, HCC, NET, GBM and breast were enrolled in expansion cohorts of up to 20 evaluable subjects. CC-223 was dosed at 45 mg once daily in 28 day cycles until disease progression. Results: As of 09 January, 2013, 101 solid tumor subjects have been treated, including NSCLC (26), HCC (25), NET (23), breast (14), and GBM (13). Results from the NSCLC, HCC, and GBM cohorts are reported here; NET results are reported separately. The most common (> 20%) related adverse events (all grades) were fatigue, rash, stomatitis, hyperglycemia, anorexia, nausea, vomiting and diarrhea. In addition, related serious adverse events included infection (1), pneumonitis (4), renal insufficiency (2) and pancreatitis (2). CC-223 dose reduction was required in > 50% of subjects with NSCLC and HCC, usually during cycle 1 or 2. Exposure-dependent TORC1 (p4EBP1) and TORC2 (pAKT) inhibition was observed across cohorts. mTOR pathway inhibition and/or decreased proliferation was demonstrated in paired tumor biopsies, but results were inconsistent. Reduction in glucose uptake (> 25% decrease in SUV) on PET imaging at day 15 was observed in 78% (14/18) of NSCLC and 69% (11/16) of HCC subjects. Partial tumor responses were observed in evaluable subjects with NSCLC (1/17; confirmed, treatment duration 36 weeks) and HCC (3/15; 1 confirmed, treatment duration 15 – 26 weeks). Disease control rate in the overall NSCLC cohort was 42% (11/26) and in the HCC cohort, 40% (10/25). GBM subjects underwent salvage resections on study and none were progression-free at 6 months. CC-223 was present in all (11/11) resected GBM tumors with plasma:tumor ratios of 16 - 77%, confirming transit across the blood-brain barrier. Conclusions: Encouraging signals of biomarker and clinical activity were observed in HCC and NSCLC. Due to the frequency of dose reductions, select additional cohorts will be enrolled at a starting dose of 30 mg QD. Clinical trial information: NCT01177397.
A phase I study of MK-2206 in combination with lapatinib in patients (pts) with advanced solid tumors.
Authors: Wisinski Kari Braun , Tevaarwerk Amye , Bell Maria , Burkard Mark E. , Eickhoff Jens C. , Wilding George , LoConte Noelle K. , Traynor Anne M. , Hoang Tien , Heideman Jennifer , Kolesar Jill , Liu Glenn 
Published: March 2020

2607 Background: The AKT protein kinase is a key mediator of signaling in the human epidermal growth factor receptor-2 (HER2) pathway. HER2 inhibition can result in feedback regulation of signaling, leading to high AKT activity. Preclinical studies demonstrate activity of combined HER2 and AKT inhibition. Lapatinib is an oral tyrosine kinase inhibitor of HER2. MK-2206 is an oral selective inhibitor of AKT with a maximum tolerated dose (MTD) of 60mg qod. Both agents cause rash and diarrhea. This study was designed to determine the MTD, dose limiting toxicities (DLTs), adverse events (AEs), clinical activity and pharmacokinetic (PK) parameters of the combination. Methods: This phase I study evaluated the safety of MK-2206 (30-60 mg qod) and lapatinib (1000-1500 mg qd) continuously. Cycles were 28 days, except cycle 1 (35 days), due to a 1 week MK-2206 lead-in to evaluate for PK interactions. Because of the continuous nature of therapy, protocol-specified intolerable grade 2 AEs were considered DLTs during cycle 1. Results: 23 pts (median age 59 [range 22-72];15 female:8 male) were enrolled. The most common malignancies were colorectal (8 pts), lung (4 pts), and breast (3 pts). 4 pts were unevaluable per protocol; 19 evaluable pts were on study a median of 8 weeks (range 3-35). 3 pts experienced DLTs. At dose level one, 1 pt had grade (gr) 3 hyponatremia and fatigue. At dose level four, 1 pt had gr 4 hyponatremia, gr 3 rash and hypocalcemia and 1 pt had intolerable gr 2 mucositis with delivery of <75% of drug. The most common AEs at least possibly related to therapy included diarrhea (gr 3-4 in 3 pts; gr 1-2 in 16 pts), nausea (gr 3 in 2 pts; gr 1-2 in 14 pts) and rash (gr 3 in 2 pts; gr 1-2 in 12 pts). The MTD was 45mg po qod of MK-2206 with 1500 mg po qd of lapatinib, exceeding biologically active doses for each agent. One pt with adrenal cortical carcinoma was on study for 6 months with stable disease (SD) and 1 pt with colorectal cancer was on study for 5 months with significant tumor marker decline and SD. PK analyses are ongoing. Conclusions: MK-2206 in combination with lapatinib is well-tolerated at biologically active single agent doses. Anti-tumor activity will be evaluated further in a dose expansion cohort in pts with advanced HER2-positive breast cancer. Clinical trial information: NCT01245205.
A first-in-human phase I trial of AR-12, a PDK-1 inhibitor, in patients with advanced solid tumors.
Authors: Mateo Joaquin , De Bono Johann Sebastian , Ramanathan Ramesh K. , Lustberg Maryam B. , Zivi Andrea , Basset Dawn , Ng Matthew , Young Anna-Mary , Garrett Michelle , Decordova Shaun , Raynaud Florence I. , Yap Timothy Anthony , Zukiwski Alexander A. , Proniuk Stefan , Shapiro Charles L. 
Published: March 2020

2608 Background: AR-12 (OSU-03012) is an oral celecoxib analogue lacking COX-2 inhibitory activity that inhibits pyruvate dehydrogenase kinase isoenzyme 1 (PDK-1), AKT and impacts the endoplastic reticulum stress pathway. Preclinical studies indicate antitumor activity of AR-12 in various models and enhanced activity in combination. We completed a first in human clinical trial to determine its safety and tolerability, maximum tolerated dose (MTD) and recommended phase II dose (RD). Secondary objectives included assessment of tumor response, pharmacokinetics (PK) and pharmacodynamics (PD) including food effect. Methods: Patients (pts) with advanced solid tumors, ECOG PS 0-1, and adequate organ function were recruited in a modified 3+3 dose-escalation study. Pts received a run-in dose of AR-12 to analyze PK-PD and food effect, followed by continuous daily (QD) dosing in 28-day cycles. A twice daily (BID) cohort was initiated based on safety data. PD analysis was performed in platelet-rich plasma (PRP) and paired tumor biopsies when feasible. Results: 35 pts received at least one dose of study drug; 30 were evaluable for dose limiting toxicities (DLT) at dose ranges 100-3200mg QD and 800-1600mg BID. No DLT were observed in the QD cohort; DLT in the BID cohort are listed in table 1. Drug-related events (NCI-CTCAE v3) included rash (G2-2pts; G3-1pt), fatigue (G2-2pts; G3-4pts), nausea (G2-7pts; G3-1pt) and bloating (G2-1pt). Cmax after single dose was dose-proportional but high PK variability was observed, likely due to inadequate disintegration and dissolution of the formulation in the stomach. At RD, partial GSK3ß inhibition in PRP after 4 hours suggests AKT-pathway modulation. Best response (RECIST v1.0) was stable disease >6 cycles for 2 pts. Conclusions: The RD based on safety data is 800mg BID. Signs of pathway modulation were observed in concordance with the expected mechanism of action but were short-lasting. Considering limited drug absorption and PK variability, a new formulation of the drug will be developed to overcome these limitations. Clinical trial information: NCT00978523. [Table: see text]
Protein pathway activation mapping guided biomarker development to identify optimal combinations of MEK inhibitor with PI3K/mTOR pathway inhibitors for the treatment of triple-negative breast cancer.
Authors: Schweber Sarah J. , Rodriguez-LaRocca Alicia G. , Calvert Valerie , Petricoin Emanuel , Horwitz Susan Band , Andreopoulou Eleni , McDaid Hayley M. 
Published: March 2020

2612 Background: Activated MAPK and PI3K pathway signaling are associated with poor prognosis in triple negative breast cancer (TNBC). Although some TNBC cell models are sensitive to MEK inhibition, feedback activation of the PI3K pathway mediates resistance. Thus, suppression of both arms of the MAPK/PI3K/mTOR network is a rational approach to targeting TNBC. Here we explore the anti-tumor efficacy of combinations of MEK inhibitor with PI3K, AKT, or mTOR inhibitors with a focus on biomarker development. Methods: Combinations of the MEK inhibitor PD-0325901 with the PI3K inhibitor GDC-0941, AKT inhibitor MK-2206, dual mTORC 1/2 inhibitor Torin 1, or the rapalog temsirolimus were evaluated in TNBC cell lines. Synergy was assessed using the combination index method of Chou and Talalay. We utilized reverse-phase protein array to map the signaling architecture of the treated lines to verify target suppression and identify pharmacodynamic biomarkers. Results: All combinations demonstrated synergy that was mediated by both suppression of proliferation and cell death in a dose-dependent manner. Cell death was delayed, peaking at least 96 hours post-dosing, and was associated with sustained suppression of target proteins in both pathways, including pERKT202/Y204, pS6rpS235/236, p4EBP-1S65, and pPRAS40T246. However, suppression of pAKT (at T308 or S473) was variable and not consistently required for cell death. Pathway mapping identified a protein network ‘signature’ specific to all combination therapies that emerged at 72 hours and was associated with cell death. Thus, all combinations appear to share common downstream effectors. All combinations showed promising efficacy and will be evaluated in a human-in-mouse model of TNBC. Conclusions: These data support therapeutic strategies for TNBC that simultaneously inhibit both arms of the MAPK/PI3K/mTOR signaling network. For continued biomarker development, we stress the importance of studying the delayed effects of combination therapy. This strategy coupled with a protein network based approach uncovered a unique functional signaling ‘signature’.
A combination of dual PI3K-mTOR inhibitor, GDC-0980, with PARP inhibitor plus carboplatin blocked tumor growth of BRCA-competent triple-negative breast cancer cells.
Authors: Dey Nandini , Sun Yuliang , Carlson Jennifer , Friedman Lori , De Pradip , Leyland-Jones Brian 
Published: March 2020

2613 Background: PARP is a promising target in the TNBC. The PI3K pathway, in addition to its pro-proliferative effects on tumor cells, also controls the repair of DSB (Kumar, 2010; Friedman, 2009; Juvekar, 2012; Ibrahim, 2012). We hypothesize that the growth of TNBC tumor will be blocked due to the inhibition of (1) HR / NHEJ, and (2) PI3K-mTOR pathway mediated survival signals following GDC-0980 (G), when combined with PARP inhibitor (impaired DNA-SSB-repair), and carboplatin (C) (increased DNA-DSB). Methods: We tested the in vivo efficacy of a combination of G with ABT888 (A) plus C in BRCA-competent TNBC cells, and compared the triple combination arm (A+C+G) with a combination arm of A+C+ pan PI3K inhibitor GDC-0941 in mice xenograft (MDA-MB231) model. Mechanistically, we tested, (1) cell survival/ proliferation (5-7 BRCA-wt and mutant cell lines) using MTT assay, CelltiterGLO, and cell cycle analyses, (2) anchorage independent and dependent clonogenic growth (3D ON-TOP and soft-agar assay), (3) apoptosis, and (4) cell signaling marker(s). Results: (1) G alone decreased the tumor growth by 40-50%. (2) The G + A + C combination blocked the growth of established tumors by 90% as compared to control(s). (3) Interestingly, G + A + C combination had markedly higher percentage of inhibition of tumor growth than the inhibition observed in the A+C+GDC-0941 arm (36%). (4) G treatment time-dependently increased cl-caspase 3, 9, and cl-PARP and increased AnnexinV positivity both time (24 and 48 hrs) and dose dependently (50 and 200 nM) in cells. (5) G when combined with A+C was most effective in inducing apoptosis in PIK3CA-mutated BT20 cells. (6) The triple combination (50 nM G+10 μM A + 10 μM C) inhibited clonogenic growth of MDA-MB231, MDA-MB468 and BT20 cells. (7)Treatment of G decreased downstream effectors of PI3K-mTOR pathway, pAKTS473, pP70S6K and pS6RP. Conclusions: Tumor growth of BRCA-competent TNBC cells is blocked by a combination treatment of G with A+C. The profound anti-tumor effect of this triple combination can be explained by the anti-proliferative and pro-apoptotic actions of the drugs. The combination of G with A+C merits further investigation in TNBC.
A first-in-human phase I study of ER-α36 modifier icaritin in patients with advanced solid tumors.
Authors: Fan Ying , Xu Binghe , Ding Xiaoyan , Ma Fei , Wang Jiayu , Yuan Peng , Luo Yang , Li Qing , Zhang Pin , Cai Ruigang 
Published: March 2020

2614 Background: ER-α36 was recently identified to be expressed in varieties of cancers and may play important roles in carcinogenesis and tumor progression. Icaritin, a natural prenylflavonoid derived from the Chinese herb Epimedium, is a first of its kind ER-α36 modifier, which demonstrated potent anti-tumor effect in multiple cancer cell lines and their xenograft models. This study aims to determine its safety, tolerability, pharmacokinetics (PK), and potential antitumor activity. Methods: This phase I study comprises phase Ia and Ib. In phase Ia part, patients with advanced breast cancer (ABC) were treated with escalating doses of Icaritin orally once daily on a continuous 28-day dosing schedule. In phase Ib part, dosing was fixed to 600 or 800mg twice daily and expansion was made to other selected malignancies including hepatocellular cancer (HCC), colorectal cancer (CRC) and intrahepatic cholangiocarcinoma (ICC) to further explore PK parameters and efficacy. Results: 24 patients were enrolled to receive Icaritin at six dose levels ranging from 50mg to 1600mg per day in phase Ia. No dose limited toxicity (DLT) was found even in the highest dose defined in the protocol, thus the maximum tolerated dose (MTD) was not reached. Only grade 1 drug-related adverse events were observed including neutropenia, ALT elevation, hypercholesteremia, fatigue, anorexia, hypertriglyceridemia, proteinuria, myalgia, hot flash and rash. PK data from the fed dosing showed 3-fold increase of Cmax and AUC compared with the fast dosing. Half life was around 2-7 hours. Among 22 evaluable subjects, no complete or partial response (CR or PR) was detected, 5 patients had stable disease(SD)for 3 months or longer. For phase Ib study, 24 patients had been enrolled. One ABC, 2 CRC and 3 ICC patients progressed after 2 months of medication. Among 7 HCC patients already evaluated, 1 obtained PR and progressed after one year of treatment and 2 remained in the study, stable for 5 months. Similar drug related toxicity profile was noted in phase Ib. Conclusions: Icaritin was generally well-tolerated without DLT across tested dose levels. Evidence of promising antitumor activity was observed in ABC and HCC. Final results will be presented at the meeting. Clinical trial information: NCT01278810.
Peripheral and tumor immune correlates in patients with advanced melanoma treated with combination nivolumab (anti-PD-1, BMS-936558, ONO-4538) and ipilimumab.
Authors: Callahan Margaret K. , Horak Christine E. , Curran Michael A. , Hollman Travis , Schaer David A. , Yuan Jianda , Lesokhin Alexander M. , Kitano Shigehisa , Hong Quan , Ariyan Charlotte Eielson , Busam Klaus J. , Feely William , Jure-Kunkel Maria , Grosso Joseph , Simon Jason S. , Korman Alan J. , Wigginton Jon M. , Gupta Ashok Kumar , Sznol Mario , Wolchok Jedd D. 
Published: March 2020

3003^ Background: Nivolumab and ipilimumab are fully human monoclonal antibodies that block the immune checkpoint receptors PD-1 and CTLA-4, respectively. In a multi-cohort, phase I study of nivolumab/ipilimumab combination therapy in melanoma patients (pts), objective response rates up to 47% were observed (NCT01024231). Putative predictive biomarkers from peripheral blood (PB) or tumor, including tumor PD-L1 expression, absolute lymphocyte count (ALC) and PB myeloid derived suppressor cells (MDSC) were evaluated. Pharmacodynamic changes in activated and effector T cells were also assessed. Methods: Tumor PD-L1 membrane expression was assessed in archival FFPE specimens by immunohistochemistry (28-8 PD-L1 antibody). ALC was measured in serial PB samples; changes in the percentage, number and phenotype of activated CD4+ and CD8+T cells and MDSC were characterized by flow cytometry. Results: PD-L1 expression was seen in 37% (10/27) of pts, using a cut-off of 5% tumor cell membrane staining. Objective responses (OR) were seen in pts with both PD-L1 negative (8/17) and PD-L1 positive (4/10) tumors. Relative to baseline, a rise in ALC was not detected, but phenotypic changes in PB T-cell subsets, including increases in the percentage of CD4 and CD8 expressing HLA-DR, ICOS and/or Ki67 were seen with combination therapy. Low ALC (<1.0 at wk 6-7) did not preclude OR as 3 of 12 pts with low ALC responded. Of pts evaluated, OR with ≥80% reduction in tumor burden at 12 wk were seen in pts with a low frequency of pretreatment PB MDSC (3/7) but no OR were seen in pts with high MDSC (0/6). Conclusions: In this small subset of pts,OR were seen independent of PD-L1 or ALC status in contrast to prior observations with nivolumab or ipilimumab, respectively. Thus, the immune response generated by combination therapy may have unique features compared to either monotherapy. The relationship between frequency of PB MDSC and reduction in tumor burden will be further explored. Further efforts in this study and in future phase III randomized studies will investigate these and other phenotypic changes in immune cell populations and their relationship to patterns of clinical activity. Clinical trial information: NCT01024231.