bluuebunny/crossref_metadata_2025_split huggingface dataset:
Therapeutic p53 gene agent in the treatment of refractory cancer cases: A phase I study.
Authors: He Xia , Xu Jianhua , Wen Jie 
Published: March 2020

2543 Background: To evaluate the benefit of adding therapeutic p53 gene agent into the standard treatment regimens for refractory cancer cases. Methods: Recombinant adenoviral human p53 gene (rAd-p53), was given intravenously at a dose of 2×1012 viral particles /day on 5 consecutive days one week before routine anti-cancer treatment start, and was repeated after an interval of 16 days. The inclusion criteria include: 1.Pathologically confirmed recurrent cancers; 2. Disseminated cases; 3. Patients with key organ metastasis; 4.Unresectable lesions; 5.Chemo- or radio-therapy resistant cases. The exclusion criteria include: 1.With severe liver, kidney, heart or hemotologic disorders; 2.Pregnancy; 3.Without informed consent. Efficacy was evaluated according to the results of contrasted MRI or CT. Results: A total of 16 patients entered the study with a median age of 59 years old (range 30-76 years), 13 were male and 3 were female. 5 were recurrent cases(4 HNSCC and 1 esophageal cancer), 5 were widely infiltrated unresectable HNSCC, esophageal carcinoma(2 cases) and undifferentiated thyroid carcinoma(1 case). 3 were disseminated cases(2 NPC and 1 Lung cancer). Two cases were breast cancer with multiple brain metastasis. One was refractory central nervous lymphoma. One patient did not finish the planned chemoradiation due to radiation-induced pneumotitis. Another one patient experienced chemotherapy delay due to A grade 4 hemotologic toxicity. 93.8% patients had shivering and fever after injection of rAd-p53. Other acute toxicities during the treatment included: leukopenia(Grade 3/4) 43.8%, thrombocytopenia (Grade 3/4) 25.0%, oral mucositis(Grade 3/4) 18.8%, vomiting(Grade 2 and above) 31.3%, ALT elevation (Grade 2 and above) 6.3%. No Cr elevation was observed. The acute toxicities were controllable and reversible. At the 3 months after treatment, PR, SD and PD rate were 56.3%, 25.0% and 18.7%, respectively. Conclusions: The therapeutic p53 gene agent can be intravenously safely added to routine anti-cancer regimens with controllable and reversible acute toxicities. A randomized controlled phase II is needed to make clear the role of the therapeutic p53 gene agent.
Efficacy of the Royal Marsden Score (RMS) to improve the selection patients (pts) considered for participation to dose-seeking phase I trial.
Authors: Favre Veronique , Meniai Fatima-Zhora , Cassier Philippe Alexandre , Gomez-Roca Carlos Alberto , Isambert Nicolas , Clisant Stephanie , Philippe Peggy , Levart Alice , Desmoulins Isabelle , Bouchet Juliette , Delord Jean-Pierre , Penel Nicolas 
Published: March 2020

2548 Background: Selection of pts entering in phase trials remains difficult. An international network of expert centers had validated the efficacy of the RMS as selection tool in such context. Nevertheless, RMS have been developed (Arkenau EJC 2008) and validated (Olmos et al. JCO 2012) in cohorts of already enrolled pts, whereas that the question of eligibility is crucial at the time of screening. We have then implemented and measured the efficacy of the RMS in 453 pts entering in the screening process in 4 expert centers. Methods: We have analyzed pts having signed the PIS/IC. RMS (0 to 3) is sum of the following prognostic factors: LDH>ULN, met. sites>2 and albumin <35 g/L. We have established the rates of enrolled pts, of pts dying within 90 days, of pts having completed PK/PD analysis, with accurate tumor assessment, having to be replaced according to RMS value. Results: Score was as follows: 0 (122/453, 27.0%), 1 (147/453, 32.4%), 2 (79/453, 17.4%), 3 (20/354, 4.4%) & not assessable (84/453, 19.2%). OS according to RMS value were 615, 299, 239 & 136 days (p=0.0001). The rates of 90-day mortality were 5.3%, 12.6%, 26.6% & 41.1% (p=0.0001). The rates of enrolled pts were 79.5%, 77.5%, 60.7% & 50.0% (p=0.001). Among enrolled pts, the rates of pts having completed the PK/PD analysis were 87.6%, 79.8%, 70.8% & 50.0% (p=0.007). Among enrolled pts, the rates of tumor assessment available were 95.8%, 88.6%, 89.5% & 70.0% (p=0.006). The rates of pts having to being replaced 4.1%, 5.2%, 2.0% & 50.0% (p=0.04). The time under study was 118, 81, 56 and 62 days (p=0.005). Conclusions: We confirm that the RMS is a reliable, easily obtained tool for selecting pts in such context. The enrollment of pts with RMS=3 is associated with a high risk of attribution rate & risk to be replaced. The time under study was significantly lower in cases of RMS =[2-3].
A phase I dose-escalation study of volasertib (BI 6727) combined with nintedanib (BIBF 1120) in advanced solid tumors.
Authors: De Braud Filippo G. , Cascinu Stefano , Spitaleri Gianluca , Pilz Korinna , Clementi Laura , Liu Dan , Glomb Patricia , De Pas Tommaso 
Published: March 2020

2556 Background: Volasertib (V) is a potent and selective cell cycle kinase inhibitor that induces mitotic arrest and apoptosis by targeting Polo-like kinases. Nintedanib (N) is a triple angiokinase inhibitor of VEGF, PDGF, and FGF receptors. Both have shown clinical activity with a manageable safety profile in patients (pts) with advanced solid tumors. This study was designed to determine the maximum tolerated dose (MTD) of V combined with N in these pts. Methods: Cohorts of 3–6 pts received V (100–450 mg IV Q3W) + oral standard dose N (200 mg BID continuously, except V infusion day). Treatment continued until clinical progression. Up to 12 pts were treated at the MTD for additional safety data. Primary endpoint was the MTD; secondary endpoints were pharmacokinetics (PK), overall safety, and preliminary efficacy. Results: 30 pts were treated (median age, 56.5 yr; ECOG PS 0/1/2, 33%/60%/7%; ≥3 prior therapies, 87%). At V doses >200 mg, 7 pts experienced 13 dose-limiting toxicities (DLTs) during cycle 1: increased alanine aminotransferase [ALT] or aspartate aminotransferase [AST], neutropenia and thrombocytopenia. The MTD was V 300 mg (Table). At the MTD, the most common all grade (Gr) adverse events (AEs) were neutropenia (69%), asthenia and thrombocytopenia (62% each), increased ALT, increased AST and diarrhea (54% each). Median (range) duration on treatment was 4 (1–18) cycles. Treatment was discontinued due to progressive disease (80%), DLT (3%) and other non-AE related reasons (17%). 2 objective responses were observed (1 complete [breast cancer] and 1 partial [NSCLC]), both with the 300 mg dose. 6 pts had SD for ≥ 6 mo. PK data will be presented at the meeting. Conclusions: MTD of V + standard dose N (200 mg BID) was determined to be 300 mg Q3W (the same as the recommended phase II single agent dose of V in solid tumors). This combination had a manageable safety profile without unexpected or overlapping toxicities and showed preliminary antitumor activity. Clinical trial information: NCT01022853. [Table: see text]
A pharmacokinetic and dose-escalating study of paclitaxel injection concentrate for nano-dispersion (PICN) alone and with carboplatin in patients with advanced solid tumors.
Authors: Ma Wen Wee , Lam Elaine Tat , Dy Grace K. , Diamond Jennifer Robinson , Zhao Yujie , Bui Lynne A. , Fetterly Gerald J. , Abramowitz Wattanaporn , Harning Ronald , Pencheva Pepi , Bhowmik Shravanti , Divekar Ganesh Harishchandra , DiRaddo Ann Marie , Eckhardt S. Gail , Adjei Alex A. , Jimeno Antonio 
Published: March 2020

2557 Background: PICN is a novel Cremaphor-free composite of paclitaxel nano-particles stabilized with polymer and lipid using Nanotecton Technology. The MTD of PICN alone was previously determined to be 295 mg/m2 iv every 3 weeks in a South Asian population. This study aimed to determine the pharmacokinetic (PK) profile of PICN alone and with carboplatin (C), and the MTD of PICN plus C. Methods: Patients (pt) with advanced solid malignancies and ECOG PS 0-1 were eligible. Part A was a PK study designed to examine cohorts of 3 pts, receiving PICN over 30 min at dose levels of 175, 260, and 295 mg/m2 every 3 weeks; PK were performed at pre-determined time-points. Part B used a ‘3+3’ dose escalation scheme, designed to determine the MTD of PICN (220, 260, and 295 mg/m2) when combined with C at AUC 6. Only standard anti-emetic pre-medications were used. Adverse events (AEs) were graded using CTCAE 4.0 and tumor response by RECIST 1.1. Results: A total of 18 evaluable pts (9 in Part A, 9 in Part B) were enrolled from 2 US academic centers. No infusion reactions were observed with PICN. No dose limiting toxicity (DLT) was observed in Part A. In Part B, the DLTs were G3 febrile neutropenia and G4 thrombocytopenia requiring platelet transfusion at PICN 260/C AUC 6. A total of 6 pts were treated at PICN 220/C AUC 6 with no DLT. G3 or worse AEs for all cycles were as follow: Part A, bilateral lower extremity weakness, neuropathy, anorexia and neutropenia; Part B, anemia, thrombocytopenia, neutropenia and empyema. Partial responses were observed in biliary(Part A; PICN 260 mg/m2), breast (Part B 220/6) and anal cancers (Part B 260/6). PK analysis showed dose-proportional increase in total plasma paclitaxel level. Conclusions: PICN alone was tolerable in the dose range evaluated. When administered with C AUC 6, the MTD of PICN was 220 mg/m2 administered every 3 weeks. Anti-cancer activity was observed in biliary, breast, and anal cancers. Final PK, toxicity and efficacy data of PICN alone and with C will be presented at the conference. Clinical trial information: NCT01304303.
Phase Ib study evaluating safety and pharmacokinetics (PK) of the oral transforming growth factor-beta (TGF-ß) receptor I kinase inhibitor LY2157299 monohydrate (LY) when combined with gemcitabine in patients with advanced cancer.
Authors: Kozloff Mark , Carbonero Rocio , Nadal Tamara , Gueorguieva Ivelina , Cleverly Ann , Desaiah Durisala , Lahn Michael M. F. , Pillay Sada , Blunt Al , Tabernero Josep , Macarulla Teresa 
Published: March 2020

2563 Background: Based on animal studies, the combination of a TGF-β inhibitor and gemcitabine is expected to enhance antitumor activity of gemcitabine. Hence, we started a combination study of LY with gemcitabine to assess the safety of this combination therapy. Methods: Gemcitabine was administered as approved and LY was given daily as intermittent dosing (14 days on/14 days off=1 cycle). A dose escalation consisting of 3 cohorts (80 mg/day, 160 mg/day, and 300 mg/day) evaluated the safety of LY in combination with gemcitabine. Toxicity was assessed using the CTCAE, version 4. Pharmacokinetic (PK) profile of LY in combination with gemcitabine was determined. Results: A total of 14 patients were evaluated (cohort 1 [n=5, 4 adenocarcinoma of colon, 1 non-small cell lung cancer, cohort 2 [n=4, adenocarcinoma, 1 each of esophageal, well differentiated, pancreas, lung], cohort 3 [n=5, 3 pancreatic, 2 rectal cancer]) in this study. The median number of cycles was 2 (range (1-6). Regardless of causality, the following treatment-emergent adverse events (TEAEs) were observed in ≥25% of patients: anemia (n=10), nausea (n=8), thrombocytopenia (n=6), neutropenia (n=6), vomiting (n=6), anorexia (n=5), fatigue (n=5), diarrhea (n=5) asthenia (n=5), pyrexia (n=4), AST increased (n=4), and constipation (n=4). Possibly related to LY, (Grade, Gr, 3/4 as mentioned) TEAEs observed were: nausea (n=5), asthenia (n=4), fatigue (n=3, 1 Gr 3), neutropenia (n=3, 1 Gr 3), anemia (n=3, 2 Gr 3 ), and in 2 patients each, thrombocytopenia (both Gr 3), headache, edema peripheral, rash, anorexia, diarrhea (1 Gr 3), mucosal inflammation, vomiting and reversible rhabdomyolysis (n=1, Gr 4). No change in the PK profile of LY was shown when LY was combined with gemcitabine. Conclusions: There were no dose limiting toxicities observed and no clinically meaningful cardiotoxicities were detected. Because of the observed manageable safety profile, LY at 300 mg/day has been advanced into a randomized Phase 2 trial in pancreatic cancer in 1st line setting to assess the antitumor activity of the combination. Clinical trial information: NCT01373164.
ProGem1: Phase I first-in-human study of the novel nucleotide NUC-1031 in adult patients with advanced solid tumors.
Authors: Ghazaly Essam Ahmed , Joel Simon , Gribben John G. , Mohammad Tariq , Emiloju Oluwadunni , Stavraka Chara , Hopkins Tom , Gabra Hani , Wasan Harpreet , Habib Nagy A , Leonard Robert C. F. , McGuigan Christopher , Slusarczyk Magdalena , Blagden Sarah Patricia 
Published: March 2020

2576 Background: NUC-1031 is a novel nucleotide (ProTide) that evades all three key cellular resistance mechanisms associated with gemcitabine (dFdC). NUC-1031 bypasses nucleoside transporters, is activated independent of deoxycytidine kinase and is resistant to cytidine deaminase-mediated degradation. NUC-1031 has demonstrated broad antiproliferative activity in vitro and in vivo. Methods: Patients with relapsed/refractory advanced solid tumors entered in sequential cohorts of up to 6 patients, with escalating doses of NUC-1031 administered as a 5-10 minute IV injection weekly or twice-weekly. Ongoing objectives are to determine recommended phase II dose, safety profile, pharmacokinetics (PK) and preliminary anti-tumor activity. Results: 8 patients (5 female, 3 male) with pancreatic (2), colorectal (2), breast (1), and ovarian (1) cancers; cholangiocarcinoma (1) and unknown primary (1) have been enrolled. Two dose levels - 500mg/m2 (4) and 1000mg/m2 (1) weekly and one dose level - 375 mg/m2(3) twice-weekly. No DLTs have been observed. Mean AUC (0 - 24 h) for NUC-1031 was 150.3 ± 84.8 µM/h (n=5). dFdC and dFdU were detected in plasma up to 24 h (range of 0 - 5.8 µM for dFdC and 0 - 14.9 µM for dFdU). NUC-1031 excreted in urine mainly as dFdU. The Table shows rapid elimination of NUC-1031 from plasma and high intracellular levels of the active gemcitabine triphosphate at 2 and 24 h. Stable disease achieved in 1 patient with rapidly progressing breast cancer. Two further patients had symptomatic relief and improved QOL, including a dramatic reduction in ascites and pain. Conclusions: PK data show NUC-1031 has ≥ 10x higher intracellular levels of the active compound, dFdCTP, and significantly lower plasma Cmax levels of the toxic metabolite, dFdU, compared to equivalent levels of gemcitabine. NUC-1031 has shown better intracellular delivery and toxicity profile than gemcitabine with some promising early indicators of clinical efficacy. Clinical trial information: NCT01621854. [Table: see text]
First-in-human trial of novel oral PARP inhibitor BMN 673 in patients with solid tumors.
Authors: De Bono Johann Sebastian , Mina Lida A. , Gonzalez Michael , Curtin Nicola J. , Wang Evelyn , Henshaw Joshua W. , Chadha Manpreet , Sachdev Jasgit C. , Matei Daniela , Jameson Gayle S. , Ong Michael , Basu Bristi , Wainberg Zev A. , Byers Lauren Averett , Chugh Rashmi , Dorr Andrew , Kaye Stanley B. , Ramanathan Ramesh K. 
Published: March 2020

2580 Background: BMN 673 is the most potent and specific inhibitor of PARP1/2 in clinical development (IC50<1nM). In tumors genetically dependent on DNA repair by homologous recombination PARP inhibition induces synthetic lethality. Methods: Pharmacokinetics (PK), pharmacodynamics (PD), safety and anti-tumor activity of BMN 673 were evaluated in a 2-stage dose-escalation study with 3-6 patients (pts)/dose level. In dose escalation (Stage 1) cycle 1 was 6 wks, with drug taken on days 1 and 8-35, for PK and PD assays, followed by daily continuous dosing in 4-wk cycles. Stage 2 (expansion at MTD) recruits pts with tumors defective in DNA repair: Ewing sarcoma, small cell lung cancer or tumors associated with BRCA mutation (mut). Results: 39 pts (33F/6M) were enrolled in 9 cohorts from 25 to 1100 µg/d that defined a MTD of 1000 µg/d. Median (range) age was 58 (19-81), PS 0 (0-1) and # of prior therapies 4 (1-13). Tumors (# with deleterious BRCA 1/2 mut) included 23 ovarian/primary peritoneal (17); 8 breast (6); 3 pancreas; 2 colon; 1 prostate (1), and 1 mullerian carcinosarcoma. 17 and 8 pts had BRCA 1 and 2 mut, respectively. Dose-limiting thrombocytopenia occurred in 1/6 and 2/5 pts at 900 and 1100 µg/d, respectively. Potentially-related adverse events in >10% of pts (# grade 1 and 2/grade 3 and 4) included fatigue (10/0); nausea (10/0); flatulence (4/0); anemia (5/2); neutropenia (4/3); thrombocytopenia (1/3); and grade 1 alopecia (10). Inhibition of PARP activity in PBMCs was observed at doses ≥ 100 µg/d. BMN 673 plasma concentrations peaked 1-2 hrs post-dose; exposure increased dose proportionally. Steady state plasma concentrations were reached by the end of the 2nd week of daily dosing; mean Cmax: 0.30 - 25.4 ng/mL and AUC0-24: 3.96 - 203 ng-hr/mL across the 25 to 1100 µg/d dose range after 28d of daily dosing. RECIST and/or CA-125 responses occurred at doses ≥ 100 µg/d in 11/17 BRCA carrier ovarian/peritoneal cancer pts. Objective responses occurred in 2/6 BRCA-carrier breast cancer pts. Conclusions: BMN 673 is well tolerated with impressive anti-tumor activity in pts with BRCA mut with a single agent recommended Phase II trial dose of 1000 µg/d due to dose-limiting thrombocytopenia. Clinical trial information: NCT01286987.
Impact of UGT1A4, UGT2B7, and UGT2B15 pharmacogenetics on tamoxifen (TAM) metabolism.
Authors: Lim Joanne Siok-Liu , Ganchev Boian , Singh Onkar , Muerdter Thomas E , Yap Yoon Sim , Ng Raymond C.H. , Wong Nan Soon , Schwab Matthias , Chowbay Balram 
Published: March 2020

2588 Background: The aims were to characterize the genetic profiles of UGT1A4, UGT2B7 and UGT2B15in Asian healthy populations (Chinese, Malay, Indians, N=80 each) and investigate the effects of these SNPs on the disposition of TAM in Asian breast cancer patients (N=202). Methods: Healthy Asian subjects and Asian breast cancer patients were genotyped for UGT1A4, UGT2B7 and UGT2B15 SNPs. Plasma levels of tamoxifen and its metabolites in Asian patients were determined via LC-MS/MS analysis. Genotypic-phenotypic differences were examined using non-parametric tests. Haplotypic effects were examined using haplotype-specific generalized linear model. Results: Screening of the 5′ upstream, exonic, exonic-intronic junctions and 3′ downstream regions identified 61, 77 and 47 SNPs in UGT1A4, UGT2B7 and UGT2B15respectively. A total of 16, 14 and 20 tag-SNPs were identified in these genes respectively and genotyped in patients. Haplotypic analysis revealed associations between LD block 1 (-1548A>G, -1531C>T, -419G>A, -219C>T, -163G>A, 142T>G, 448T>C, 804G>A, IVS1+196T>C, IVS1+346T>G, IVS1+414A>G, IVS2+307A>G) and higher plasma Tam-N-Gluc level and MRTAM-N-Gluc/TAM after adjustment for significant covariates. The median (range) MRTAM-N-Gluc/TAM was 2.1- and 1.9-fold higher among patients carrying one and two copies of H2 (GCATAGCACTGG), respectively, compared to patients who carried two copies of H1 haplotype (ACGCGTTGTTAA) [H1/H1 vs H1/H2 vs H2/H2: 0.35 (0.11 - 2.09) vs 0.74 (0.19 - 3.60) vs 0.66 (0.52 - 1.66), P < 0.0001]. Similar association was observed between H2 and Tam-N-Gluc level [H1/H1 vs H1/H2 vs H2/H2: 0.75 (0.15 - 4.45) vs 1.29 (0.19 - 9.20) vs 1.66 (0.62 - 2.83) ng/ml, P= 0.004]. UGT2B15 LD block 3 (1568A>C, *168C>T, *186A>T, *+630C>G and *+888A>G) was associated with modest decrease and increase in (E)-END and MRZ-NDM-4-O-GLUC/E-END, respectively. UGT2B7haplotypes were not associated with O-glucuronidations of 4-OHT and END. Conclusions: This study highlights the involvement of UGT1A4 haplotypes in the variability in TAM N-glucuronidation while UGT2B7 and UGT2B15 variants played limited role in the variabilities of O-glucuronidations of 4-OHT and END in Asian breast cancer patients. Clinical trial information: 0822570P.
Dose-dependent pharmacokinetic (PK) interaction of pegylated liposomal doxorubicin (PLD) with escalating doses of veliparib in a phase I study.
Authors: Pothuri Bhavana , Muggia Franco , Sparano Joseph A. , Blank Stephanie V. , Curtin John Patrick , Chuang Ellen , Hershman Dawn L. , Chen Alice , Liebes Leonard 
Published: March 2020

2591 Background: PARP1 inhibition enhances the effects of DNA-damaging agents such as doxorubicin. We sought to investigate PK of PLD in a phase I study of veliparib (ABT-888, V) and PLD in patients (pts) with recurrent ovarian, fallopian tube, and primary peritoneal, and triple negative breast cancers. No prior PK interactions have been described in V clinical trials. Methods: Complete blood samples on day (D) 1 (pre-PLD and 1 hr post PLD), D 8, D 22 on cycle 1 and 2 of treatment in pts receiving PLD 40 mg/m2, day (D) 1 and V D1-14 at varying dose levels of 50,100,150, 200, 300, 350 mg twice daily, were collected in 25 of 31 pts enrolled to a previously reported dose finding phase I study of V and PLD (SGO2012). Plasma PLD levels were measured by HPLC methodology detailed by Gabizon et al Cancer Chemo Pharmacol 2008, 61:695. PK parameter estimates were obtained using non-linear modeling programs available in Winnonlin Ver 5.3. Affect of V dose on PK parameters was estimated with linear regression analysis. Due to a higher degree of GI toxicity with V dosages > 200 mg, we utilized a cut-off of 200 mg for V. PK parameters in the group with dosages greater than or equal to 200 mg (high V, n=18) and those less than 200 mg (low V, n=7) were compared, utilizing an unpaired, 2 sided t-test. Results: PLD clearance (CL) was reduced, half-life (hL) was increased, and AUC/mg was increased with higher dosages of V when compared to historical published data. We noted a positive correlation of the auc/mg dose, p=0.001 and a negative correlation with the CL, p=0.001 and increasing V dose. When analyzed as low and high V groups, the mean ± SEM hL (hrs) was significantly lower in the low V when compared to the high V group, 83.2 ± 11.7 vs 108.6 ± 6.0(p =0.042) , and the mean PLD clearance (ml/h)was greater in the low V versus the high V group 35.9 ± 5.6 vs 14.2 + 1.0, P<.0001. Similarly the AUC/mg dose (mg x h/L) was significantly lower in the low vs high V groups, 35.0 ±5.2 vs 74.9 ± 4.4, P<0.0001. Conclusions: Higher exposure of PLD is noted with V at doses greater than or equal to 200 mg twice daily. An expansion cohort with patients receiving PLD alone in cycle 1, and PLD + V 200 mg twice daily in subsequent cycles, will validate the presence of a PK interaction. Clinical trial information: NCT01145430.