bluuebunny/crossref_metadata_2025_split huggingface dataset:
Adherence to novel oral anticancer therapies in the phase I setting: The Royal Marsden experience.
Authors: Chenard-Poirier Maxime , Ang Joo Ern , Harris Samuel John , Ingles Garces Alvaro Henrique , Seeramreddi Satyanarayana , Sundar Raghav , Collins Dearbhaile Catherine , Ameratunga Malaka , Lopez Juanita Suzanne , De Bono Johann S. , Banerji Udai 
Published: September 2018

2542 Background: The use of oral anticancer therapies has increased substantially in recent years. Nonadherence can impair the efficacy of such therapies as well as confound the interpretation of toxicity and pharmacokinetic data in phase I trials. However, there is a paucity of data regarding adherence patterns and barriers in this specific setting. Methods: We included patients treated in Phase I trials involving oral investigational medicinal products (IMPs) in the Drug Development Unit, Royal Marsden Hospital, UK, between 2012 and 2014. Patient, disease and treatment characteristics as well as compliance data from prospectively collected trial diary cards and drug accountability were recorded. Relationships between adherence rate and other variables were explored using logistic regression. Results: We collected data for 2819 patient-weeks, pertaining to 169 patients treated on 18 different phase I trials. Median age was 61 years (range 18-79), females predominated (60%), median number of previous systemic therapy was 3 (0-12) and median time on trial was 9 weeks (0.3-212.4). Hundred-percent adherence rate was 88% in the first cycle and 79% overall. Nonadherence occurred in 83 of 2819 patient-weeks (3.0%); including 75 (2.7 %) missed doses and 8 (0.3 %) overdoses. In univariate analysis, longer time on trial and a continuous treatment schedule were associated with poorer adherence, whereas fasting requirements pre- or post-dosing was associated with improved adherence. Known intracranial metastases, number of concomitant medications and opiates or anti-emetics use were not significantly associated to adherence. In multivariate analysis, fasting requirements (OR 5.347, 95%CI : 1.443-20.019, p = 0.012) and longer time on trial (OR 0.98, 95%IC : 0.961-0.996, p = 0.017) were statistically significant. Conclusions: This is the first report on adherence rates to oral anticancer IMPs in a large phase I trial population. Our observed adherence rates are at the higher end of published data in the general cancer population. Factors influencing adherence in phase I trials appear to be distinct, with fasting requirements being a unique finding. These findings may impact future early-phase trial design and conduct.
Pharmacokinetics (PK) and pharmacodynamics (PD) of a novel carcinoembryonic antigen (CEA) T-cell bispecific antibody (CEA CD3 TCB) for the treatment of CEA-expressing solid tumors.
Authors: Melero Ignacio , Segal Neil Howard , Saro Suarez Jose M. , Ros Willeke , Martinez Garcia Maria , Calvo Emiliano , Moreno Victor , Ponce Aix Santiago , Marabelle Aurelien , Cleary James M. , Hurwitz Herbert , Eder Joseph Paul , Jamois Cancize , Belousov Anton , Bouseida Said , Sandoval Federico , Bacac Marina , Nayak Tapan K. , Karanikas Vaios , Argiles Guillem 
Published: September 2018

2549 Background: CEA CD3 TCB (RO6958688) targets CEA on tumor cells and is agonistic for CD3e on T cells. In mouse models, CEA CD3 TCB displays potent anti-tumor activity, leads to increased intra-tumoral T cell infiltration and activation and up-regulates the PD-1/PD-L1 pathway. Methods: Biodistribution was assessed in mice using SPECT/CT. Patient (pts) samples correspond to 2 dose-escalation studies in CEA+ solid tumors. Study 1 (S1): single agent weekly (qW) (0.052 to 600 mg, iv, n = 80), and Study 2 (S2): combination of RO6958688 qW (5 to 160 mg, iv) with 1200mg atezolizumab q3W (n = 38). Analytical methods: PK - population modeling approach; anti-drug antibodies (ADA) - ELISA; immunophenotyping in peripheral blood (PB) by flow cytometry (FCM), in pre- (BSL) and on-treatment (OT) biopsies by immunohistochemistry (IHC) and FCM; plasma cytokines - multiplex assays; PD-L1 - SP142 assay. Results: In mice, RO6958688 preferentially accumulated in CEA+ tumors. In pts with no ADAs tested thus far in both studies (S1 29; S2 21), RO6958688 showed near linear PK and exposure. In S1, OT biopsies demonstrated a statistically significant increase in density and activation profile of T cells (CD3: 2.6-fold, n = 21; CD3/CD8: 3.7 fold, n = 17; CD3/Ki67: 4-fold, n = 20; CD8/PD1: 1.7-fold, n = 15) without dose-dependence. In S2, preliminary data of T cell density (5-80mg) were similar to S1 (2-fold). In S1, a significant correlation was observed between treatment-induced tumor lesion reduction and increases of OT CD8/CD25 fluorescence intensity from BSL (p = 0.028). PD-L1 expression increased in OT biopsies in both studies. In S1, from week 4, a moderate expansion of activated CD8 T cells (HLA-DR/Ki67) but not of CD4, was detected in PB at doses > 60mg ( > 3.3 fold). Transient increases of several cytokines were seen in both studies with levels peaking within 24hrs. Conclusions: PK and PD results consistent with tumor inflammation and mechanism of action support that RO6958688 is the first tumor-targeted T cell bispecific to show intra-tumoral biological activity in pts with CEA+ solid tumors. Updated data will be presented. Clinical data are reported separately.
An open-label expanded-access study to evaluate the safety, tolerability, and pharmacokinetics of trifluridine/tipiracil in patients with advanced solid tumors and hepatic impairment.
Authors: Saif Wasif M. , Rosen Lee S. , Rudek Michelle A. , Sun Weijing , Shepard Dale Randall , Becerra Carlos , Yamashita Fumiaki , Bebeau Paul , Winkler Robert 
Published: September 2018

2559 Background: The Phase 3 RECOURSE study showed that trifluridine/tipiracil (FTD/TPI) was effective in the treatment of refractory metastatic colorectal cancer (Mayer et al. N Engl J Med 2015;372:1909-19). A Phase 1 open-label study evaluated the safety and pharmacokinetics of FTD/TPI in patients with advanced solid tumors and varying degrees of hepatic impairment to inform dosing recommendations for these patients. Methods: Patients aged ≥18 years with advanced solid tumors, an Eastern Cooperative Oncology Group performance status ≤2, normal hepatic function, and mild, moderate, or severe impaired hepatic function according to the National Cancer Institute criteria were enrolled. Patients received FTD/TPI 35 mg/m2 orally twice daily on days 1-5 and days 8-12 of each 28-day cycle, except for those with severe impaired hepatic function (dose was to be determined). Results: 24 patients were enrolled to normal (n=8), mild (n=10), and moderate (n=6) groups. Study enrollment was stopped as 5/6 patients in the moderate group experienced elevated bilirubin levels (grade ≥3). The other baseline characteristics were similar across groups. Overall, 12 patients (50%) had at least 1 adverse event leading to study discontinuation: 2 in normal, 5 in mild, and 5 in the moderate hepatic impairment groups. Pharmacokinetic results are summarized in the table. Conclusions: The exposure to FTD or TPI was not increased by hepatic impairment and the patients who experienced grade 3 and 4 increased total bilirubin were not overexposed to FTD or TPI. Clinical trial information: NCT02301104. [Table: see text]
Vitamin K epoxide reductase complex subunit 1 (VKORC1): A pharmacogenomic predictor of response and survival in patients (pts) on triplet hepatic artery infusion (HAI) and intravenous cetuximab (IV-Cet) for initially unresectable liver metastases from colorectal cancer (uLM-CRC) (EU trial OPTILIV).
Authors: Levi Francis , Saffroy Raphael , Karaboue Abdoulaye , Desterke Christophe , Boige Valerie , Hebbar Mohamed , Smith Denis Michel , Bouchahda Mohamed , Innominato Pasquale , Taieb Julien , Carvalho Carlos , Guimbaud Rosine , Focan C. N. J. , Ducreux Michel , Adam Rene , Lemoine Antoinette 
Published: September 2018

2569 Background: The HAI of Irinotecan-Oxaliplatin-5-Fluorouracil (IFO) with IV-Cet achieved 29.7% complete uLM-CRC resections (R0+R1) and an overall median survival (OS) of 25.7 months in previously treated pts (Lévi, Ann Oncol 2016). Methods: To identify pharmacogenomic predictors of outcomes, 207 single nucleotide polymorphisms (SNPs) from 34 pharmacology genes were analysed in blood mononuclear cells (ADME PGx, MassArray platform, Sequenom, USA). Relations between SNPs and tumor response, R0+R1, survival, and toxicities were tested using adjusted Mann Whitney, Fisher Exact, Log Rank tests and Hardy-Weinberg Equilibrium. Results: Pts (16F;36M; 33-76 yo; WHO performance status 0-1) received protocol treatment as 2nd (21 pts) or 3-4thline (31 pts). VKORC1 SNPs in promoter (rs9923231) and intron (rs9934438) were consistently associated with early and objective responses, and overall survival. For rs9923231, T/T (N = 8) as compared to C/T (N = 21) had greatest chance of achieving early response (50% vs 5%, p = 0.029) or 4-y survival (46% vs 0%, p = 0.006). VKORC1 SNPs also related to HA thrombosis (rs992331, T/T, 77% vs C/C, 30%, p = 0.04). In contrast, NAT2 SNPs (rs1041983 and rs1801280) were associated with up to 5-fold differences in R0-R1 resection rate. Statistically significant associations (p < 0.05) of SNPs with clinical outcomes were found for oxydo-reduction (CYP2E1 and HA thrombosis; CYP2C9 and diarrhea; CYP2C19 and diarrhea, fatigue, and early response), conjugation (UGT1A1 and diarrhea; NAT2 and fatigue); and transport (ABCB1 or SLC0B3 and neutropenia; SLC22A1 and diarrhea; SLC 15A2 and early response). Conclusions: VKORC1 was highlighted for the first time, as a pharmacogenomic predictor of HAI efficacy for LM-CRC. Conversion-to-resection was associated with NAT2 polymorphism. VKORC1 γ-carboxylates vitamin K-dependent proteins. Its polymorphism guides personalized warfarin dosing. VKORC1 SNPs determination could help identify the uLM-CRC pts who best benefit from intensive HAI therapy. Clinical trial information: NCT00852228.
TAX-TORC: A phase I trial of vistusertib (AZD2014) in combination with weekly paclitaxel with integrated pharmacodynamic (PD) and molecular characterization (MC) studies.
Authors: Sundar Raghav , Basu Bristi , Wilson Richard H. , Spicer James F. , Jones Robert Hugh , Krebs Matthew , Brada Michael , Talbot Denis Charles , Steele Nicola , Hall Emma , Tovey Holly , Carreira Suzanne , de Oliveira Flavia M , Swales Karen E , Balarajah Geetha , Dawes Joanna C , Parmar Mona , De Bono Johann S. , Banerji Udai 
Published: September 2018

2571 Background: In ovarian cells isolated from ascites, p-S6K levels were found to correlate with resistance to chemotherapy. We hypothesised that inhibiting p-S6K signalling with dual m-TORC1/2 inhibitor vistusertib (V) in addition to paclitaxel (P) would improve outcomes of patients with high-grade serous ovarian cancer (HGSOC). Methods: In the dose escalation part, weekly P 80mg/m2IV (6/7 weeks) was evaluated in combination with two schedules of V; Schedule A: V (25, 50 or 75mg) BID PO on day(D) 1-3/week and Schedule B: V (75 or 100mg) BID PO D1-2/week. This was followed by an expansion cohort in 25 HGSOC patients. Results: Dose limiting toxicities in Schedule A were fatigue and mucositis and in Schedule B were diarrhoea, rash and fatigue. The AUC, Cmax and half-life of V in the 50mg-cohort were 2821ng.hr/ml, 926ng/ml and 3hrs, comparable to single agent studies. PD analysis (from six 50mg-cohort patients) in platelet-rich plasma showed increased phosphorylation of Ser473 AKT following P induction (1.4 fold, p = 0.1378). Following addition of V to P, phosphorylation levels 4hrs post-treatment with V fell significantly to 53% of pre-dose levels (p = 0.0495). This was 61% lower than the corresponding time point following P alone. Based on toxicity, pharmacokinetic and PD evaluation, recommended phase 2 dose was established as P 80mg/m2 D1 and V 50mg BID D1-3 for 6/7 weeks. In the HGSOC expansion, 96% of patients had relapsed within 12 months of last platinum therapy and 100% had received previous paclitaxel, with a median of 3 previous lines of treatments. RECIST and GCIG CA125 response rates were 13/25 (52%) and 15/25 (60%) respectively, with median progression free survival of 5.5 months. MC was performed on archival tumor tissue of 24/25 HGSOC expansion cohort patients, with the most common mutations occurring in p53 (100%), BRCA (17%), and MUC16 (17%). ATM mutations occurred in 17% (n = 4), 3 of whom had a response. Conclusions: We report a highly active combination of paclitaxel with an intermittent schedule of vistusertib in patients with HGSOC. This combination is now being evaluated in a randomised controlled trial for this indication. Clinical trial information: NCT02193633.
Investigating novel resistance mechanisms to third generation EGFR TKI osimertinib in non-small cell lung cancer patients using next generation sequencing.
Authors: Ou Qiuxiang , Wu Xue , Bao Hua , Tong Xiaoling , Wang Xiaonan , Zhang Xian , Chang Zhili , Mao Yu , Shao Yang , Zhou Caicun 
Published: September 2018

2572 Background: Third generation epithelial growth factor receptor ( EGFR) tyrosine kinase inhibitor (TKI) osimertinib (AZD9291) has proven effective in Non-small cell lung cancer (NSCLC) patients who have developed EGFR T790M-mediated resistance to other EGFR TKIs. Unfortunately, a majority of patients still undergo progressed disease after receiving osimertinib treatment. Acquired EGFR C797S mutation has been identified as one major mechanism; however, resistance mechanisms of remaining cases are still largely unknown. Methods: Using next generation sequencing (NGS) targeting 416 cancer-relevant genes, we analyzed the mutation profiles of 99 NSCLC patients that were clinically resistant to osimertinib. Results: In addition to the notable EGFR C797 variants (22%), L792 mutations were identified in 10% of patients, and a further 7% cases carry L718 mutations. Further analysis of 14 patients with paired pre-treatment samples confirmed that these EGFR mutations were acquired during treatment. Interestingly, all L792 mutations are in cis with T790M and in trans with C797 mutations (when present in the same patient). 2 out of 10 L792-positive patients and 6 out of 7 L718-positive patients did not have co-existing C797 mutations, suggesting C797-, L792- and L718-mutated cells may represent different resistant clones. In vitro experiments demonstrated that L792 and L718 mutants also increase osimertinib IC50, and therefore confer their resistance. Besides secondary EGFR mutations, alterations in other key genes such as MET, KRAS, ERBB2 and PIK3CA may also contribute to osimertinib resistance. Notably, MET and KRAS amplifications are present only in patients without above EGFR secondary mutations. Conclusions: In this study, we identified secondary mutations on C797, L792 or L718 residues of EGFR in 29% of osimertinib-resistant patients. Combined with in vitro study, our data strongly suggest that L792 and L718 mutations are likely to alternatively cause osimertinib resistance. Furthermore, MET and KRAS amplification may serve as bypass resistance mechanisms in patients who are EGFR C797-, L792- and L718-wild type.
Phase 1 study of the p53-MDM2 inhibitor AMG 232 combined with trametinib plus dabrafenib or trametinib in patients (Pts) with TP53 wild type (TP53WT) metastatic cutaneous melanoma (MCM).
Authors: Moschos Stergios J. , Sandhu Shahneen Kaur , Lewis Karl D. , Sullivan Ryan J. , Johnson Douglas Buckner , Zhang Yilong , Rasmussen Erik , Henary Haby A. , Long Georgina V. 
Published: September 2018

2575 Background: Large sequencing studies in MCM have shown a TP53WT incidence of approximately 80%. In preclinical TP53WT melanoma models, the oral p53-MDM2 inhibitor AMG 232 exhibited synergistic, cytotoxic-type antitumor activity when combined with MAPK inhibitors. This phase 1 study assessed the toxicity (CTCAE 4.03), maximum tolerated dose (MTD), pharmacokinetics (PK), and preliminary antitumor activity (RECIST 1.1) of AMG 232 plus trametinib (T) and dabrafenib (D) (BRAFV600-mutant) or T (BRAFV600-WT) in pts with TP53WT MCM. Methods: Using 3+3 dose escalation design, pts with advanced TP53WT (using a CLIA-approved assay) MCM received AMG 232 PO QD for seven days of each 3-week cycle (7/21) at 120, 240, or 480 mg plus either T 2 mg PO QD and D 150 mg PO BID (Arm 1; BRAFV600-mutant) or T 2 mg QD (Arm 2; BRAFnonV600-mutant). Results: At the time of this analysis, 21 pts (median age, 58 y [range 24–76]; male, n = 11; at least 2 systemic treatments, n = 15) were treated. Arm 2 enrolled first: AMG 232 120 mg (n = 6), then 240 mg (n = 6). Due to chronic grade (G) 2 gastrointestinal toxicity, an intermediate dose (180 mg; n = 3) was determined as the preliminary MTD. Arm 1 enrolled at AMG 232 120 mg (n = 4), then 180 mg (n = 2). The most common reasons for AMG 232 withdrawal were disease progression (n = 8) and AEs (n = 4); 6 pts remain on AMG 232. All 21 pts had treatment-related AEs (TRAEs); the most common TRAEs were nausea (n = 18), fatigue (n = 17), diarrhea (n = 14), and vomiting (n = 13). The only DLT (Arm 2; 240 mg) was G 3 pulmonary embolism. Preliminary PK analysis suggests that AMG 232 exposure (area under the curve) is similar to that as monotherapy at the same dose, with no apparent drug-drug interaction between AMG 232 and T; analysis of D and T PK is ongoing. Of 21 pts, 6 had partial response (Arm 1/2, n = 4 [67%]/2 [13%]), 13 had stable disease (Arm 1/2, n = 2 [33%]/11 [73%]), and 2 progressed (Arm 1/2, n = 0/2 [13%]) as best response; 17 had tumor reduction (Arm 1/2, n = 6 [100%]/11 [73%]). Conclusions: In this population of pts with MCM, AMG 232 combined with D and/or T during DE was tolerable up to 180 mg QD 7/21 days, showing an acceptable PK profile and early antitumor activity. Clinical trial information: NCT02110355.
Phase 1 dose escalation study of the folate receptor-targeted small molecule drug conjugate EC1456.
Authors: Harb Wael A. , Edelman Martin J. , Chambers Setsuko K. , Garland Linda L. , Armour Alison , Wang Ding , Goss Glenwood D. , Sachdev Jasgit 
Published: September 2018

2576 Background: The folate receptor (FR) is highly expressed in a variety of cancers including adenocarcinoma of the lung, but is expressed at low levels in most normal tissues, making it a potential target for therapeutic intervention. EC1456 is an FR-targeted small molecule drug conjugate (SMDC) consisting of folic acid chemically attached through a bio-releasable linker system to a potent microtubule inhibitor, tubulysin B hydrazide (TubBH). EC1456 binds to, and is endocytosed by the FR-expressing cancer cell to deliver TubBH. Following endocytosis, the FR recycles back to the membrane surface every 18-24 hours. Therefore alternative EC1456 schedules will be evaluated for safety, pharmacokinetics, and therapeutic benefit. Methods: Part A (dose escalation) is being evaluated in unselected patients (pts) with advanced solid tumors. 4 schedules (3-week cycle) are being evaluated: BIW (twice weekly); QW (once weekly); CWD (continuously weekly); QIW (four times a week). The primary objective of Part A is to determine the RP2 dose and schedule of EC1456. Part B (expansion) will confirm the MTD and RP2 dose and evaluate efficacy of EC1456 in 99mTc-etarfolatide-selected NSCLC patients in up to three schedules. Results: 74 Part A pts are evaluable for toxicity. Median age is 68 (range: 26-88); 53 pts are female. Toxicities are primarily Grade (Gr) 1 and 2. Common treatment-related adverse events (TRAE) are gastrointestinal, fatigue, metabolic changes, alopecia, and headache. 5 Gr 3 DLTs have been observed: infusion reaction (4.5 mg/m2 QW), headache (10.0 mg/m2 QW), and abdominal pain (7.5 mg/m2 BIW, 12.5 mg/m2 QW and 10.0 mg/m2CWD). TRAEs are summarized in the table for each schedule. Durable stable disease of 12 wks or longer has been observed in 12 pts (6 BIW and 6 QW). Conclusions: All Part A EC1456 schedules have been well tolerated. RP2 dose for BIW is 6.0 mg/m2 and QW is 12.5 mg/m2; dose escalation is ongoing for CWD and QIW. Early signs of efficacy in an unselected pt population may be suggested by durable stable disease. Safety and efficacy evaluation in the 99mTc-etarfolatide-selected NSCLC population (Part B) is ongoing. Clinical trial information: NCT01999738. [Table: see text]
A phase 1/2 study of intermittent, high dose sunitinib in patients with advanced solid tumors.
Authors: Rovithi Maria , Labots Mariette , Honeywell Richard , Ten Tije Albert J. , Ruijter Rita , Skardhamar Mikkjal , Peters Godefridus J. , Voortman Jens , Verheul Henk M.W. 
Published: September 2018

2591 Background: Despite widespread clinical integration, refinement of treatment with sunitinib is actively pursued. Sub-therapeutic blood levels rather than true resistance and tumor adaptation through drug accumulation have been accounted as reasons for treatment failure. Based on our preclinical data with high dose sunitinib and prospective analyses supporting the concept of intermittent dosing, we designed a phase 1 trial to investigate the feasibility and tolerability of high dose, once weekly (1w) or once every two weeks (2w) sunitinib (NCT02058901). Methods: Eligible were patients (pts) with advanced solid tumors, refractory to standard treatment, measurable disease, WHO ≤ 1. Sunitinib was administered orally 1w or 2w. Starting dose was 200 mg, with cohorts escalating in 100 mg steps until maximum tolerated dose (MTD). Response was evaluated by RECIST 1.1. Treatment continued until progression or unacceptable toxicity. Dedicated PK sampling was performed. Sunitinib plasma concentration was measured by LC-MS. Results: 34 (w) and 24 (2w) pts were included, predominantly with mCRC [56% (1w) and 55% (2w)]. MTD was set at 300 mg (1w) and 700 mg (2w). Most common adverse events were fatigue (79%, one pt with G3), nausea (71%, all G1-2), anorexia (29%, all G1-2). Median PFS of evaluable pts was 2.7 mo (1w) and 2.6 mo (2w), while 39% pts (1w) and 25% pts (2w) had PFS > 5 mo. CT scans in pts with treatment benefit showed extensive tumor necrosis. Mean sunitinib plasma Cmax was 190 [300 mg (1w), range: 185-295] and 476 ng/mL [(700 mg (2w), range: 323-580]. Accumulation was minimal. Conclusions: Once weekly or once every two weeks, high dose sunitinib is feasible and clinically efficacious in heavily pretreated pts with advanced solid tumors, while toxicity remains well manageable. Importantly, no accumulation was recorded and sunitinib exposure was significantly increased, compared to the universal, flat dose. Since increased sunitinib exposure has been correlated to improved outcome, we consider this alternative scheduling as promising strategy to produce enduring clinical benefit in a wider patient population. Expansion cohorts are ongoing. Clinical trial information: NCT02058901.