bluuebunny/crossref_metadata_2025_split huggingface dataset:
BBI608-201GBM: A phase Ib/II clinical study of napabucasin (BBI608) in combination with temozolomide (TMZ) for adult patients with recurrent glioblastoma (GBM).
Authors: Mason Warren P. , de Robles Paula , Borodyansky Laura , Hitron Matthew , Ortuzar Waldo Feliu , Khan Waheed , Xu Bo , Li Wei , Li Youzhi , Li C J 
Published: September 2018

e13525 Background: Napabucasin, a first-in-class cancer stemness inhibitor in clinical development, suppresses cancer stemness by targeting STAT3-driven gene transcription. Pre-clinically, potent and broad-spectrum anti-cancer activity was observed in vitro and in vivo, alone and in combination with other agents. PK studies demonstrated napabucasin penetration in the murine orthotopic GBM model. Methods: A phase Ib/II open-label, multi-center study in pts with GBM at first recurrence who have not received bevacizumab, was performed to determine safety and preliminary activity of napabucasin administered orally at 480mg BID po in combination with TMZ 150mg/m²/day po; days 1 through 5 of each 28 day cycle, until disease progression or unacceptable toxicity. A 6-patient safety cohort was planned to evaluate the occurrence of DLT during the first 28 days of combination treatment with napabucasin and TMZ. 4 additional patients have been enrolled under the RP2D expansion phase. Results: 11 pts have been enrolled to date; no DLT was observed in the safety cohort and the RP2D of the combination is 480 mg BID for napabucasin. The safety profile was consistent with that of each agent as monotherapy and most common AEs included grade 1/2 diarrhea, nausea, abdominal cramps, and vomiting. Two patients requested to withdraw treatment due to concurrent conditions and AE s. 9 patients were evaluable by RANO; Disease Control Rate was observed in 5 patients (55.5%) of which 4 achieved PR (44.4%) and 1 achieved SD (11.1%). The Overall response rate was 44.4% in the evaluable patients. Conclusions: This phase Ib/II study demonstrated that napabucasin at 480 mg BID can be safely combined with temozolomide at full dose and showed encouraging anti-tumor activity in patients with recurrent Glioblastoma. Clinical trial information: NCT02315534. [Table: see text]
A phase I study of safety and pharmacokinetics of NanoBB-1-Dox in patients with advanced solid tumors.
Authors: Filon Olga , Krivorotko Petr , Kobyakov Grigory , Razjivina Viktoria , Maximenko Olga , Gelperina Svetlana , Kreuter Joerg 
Published: September 2018

e13537 Background: NanoBB-1-Dox is a novel drug candidate for systemic chemotherapy of glioblastoma multiforme (GBM). It is a nanoparticle-based formulation of doxorubicin, which enables passage of the drug across the blood-brain barrier and delivery to the tumor inside the brain. Preclinical studies demonstrated that NanoBB-1-Dox enabled considerable growth inhibition of an intracranially implanted 101.8 glioblastoma in rats and long-term remission in >20% animals, whereas the conventional doxorubicin formulation was only marginally effective. Methods: 21 patients with advanced solid tumors (18 with advanced breast cancer, 34 with GBM) were enrolled in the study. The objectives of the study were: 1) to evaluate the safety and pharmacokinetics (PK), 2) to determine the maximum tolerated dose (MTD). A standard “3 + 3” design with 7 dose levels (4, 24, 36, 48, 60, 75 and 90 mg/m2) was used. Each patient received a single i.v. infusion of NanoBB-1-Dox. Doxorubicin serum concentrations were measured immediately before the infusion, and 2 min, 10 min, 20 min, 40 min, 1 h, 2 h, 4 h, 6 h, 8 h, 12 h, 24 h, 48 h, 72 h, 168 h after the infusion. Results: The PK analysis demonstrated that AUC0-t of doxorubicin after the NanoBB-1-Dox infusion increased in parallel with the dose level from 121.7 to 2054.4 h x ng/ml. T1/2 varied from 45 to 75 h without dose dependence. NanoBB-1-Dox was well tolerated without dose limiting toxicity even at the highest dose of 90 mg/m2, so the MTD was not achieved. The most common AEs included leukopenia, lymphopenia, neutropenia, thrombocytopenia, anemia, nausea, and alopecia. In general, the AE rate and intensity increased with the dose level reaching the maximum at a dose of 90 mg/m2. Only hematological AEs were severe according to CTCAE 4.03. No SAEs were reported. Conclusions: NanoBB-1-Dox after a single i.v. infusion in patients with advanced solid tumors is well tolerated and is characterized by a non-linear PK profile. NanoBB-1-Dox will be investigated in a phase II study in patients with GBM as a second line therapy. [Table: see text]
Blood trypsin proteinases as a new additional test in differential diagnosis of brain tumors.
Authors: Kozlova Larisa , Frantsiyants Elena Mikhaylovna , Tkalya Lyudmila Dmitriyevna , Rostorguev Eduard Evgenevich , Atmachidi Dmitriy P. , Kavickij Sergey E. , Kuznetsova Natalya S. , Porksheyan David H. 
Published: September 2018

e13543 Background: Activation of trypsin-type proteinases in cancer is a proven fact. Activity of enzymes synthesized and secreted by a malignant tumor is generally not controlled by endogenous inhibitors. Benign tumors do not come into metabolic conflict with the carrier body, at least prior to their possible malignant transformation. The purpose of the study was to analyze changes in activity of trypsin proteinases (ATP) in the blood plasma of patients to determine possible application of the parameter as an additional test in the differential diagnosis of brain tumors. Methods: The blood plasma of 164 patients was studied: 37 benign brain tumors, 74 primary glioblastomas (G) and 53 brain metastases (MTS) from breast cancer. ATP was determined before treatment using the U-2900 UV Solutions double-beam spectrophotometer (USA). The results were compared to the values in 39 healthy donors (N). The data were processed using the Statistica 10 program. Results: ATP did not differ from N in 37 of 164 patients (22.6%). After removal of the brain tumors, histological examination of surgical material showed benign brain tumors in all 37 cases. ATP in 74 of 164 patients (45.1%) exceeded N by 3.8-5.3 times (on average 4.4±0.3). Histological examination after removal of the brain tumors showed primary G in all 74 cases. ATP was 5.9-9.4 times higher than N (on average 7.3±0.5) in 53 of 164 patients (32.3%). Histological examination after removal of the brain tumors showed MTS in all 53 cases. Conclusions: ATP value similar to N indicates a benign tumor. ATP increase by 3.8-5.3 times shows the presence of a primary malignant tumor. ATP increase by 5.9-9.4 times supposes MTS.
Bevacizumab for the treatment of radiation necrosis in melanoma patients.
Authors: Glitza Isabella Claudia , Amaria Rodabe Navroze , D'Souza Neil Mark , Jiang Wen , Li Jing 
Published: September 2018

e13548 Background: Radiation necrosis (RN) can be a late complication of radiotherapy for CNS malignancy, often associated with neurological morbidity. High dose corticosteroids or surgical resection have been the standard of care treatment (tx), but protracted steroid course can lead to significant side effects and surgery is not always feasable. While there is evidence that the anti-VEGF antibody bevacizumab (Bev) can be effective for RN in other cancer types, evidence supporting its use for RN in melanoma patients (pts) is lacking, due to known risk of spontaneous bleeding in melanoma brain metastasis (MBM) and increased bleeding risk with Bev. Methods: We retrospectively identified 6 melanoma pts who received Bev for RN, and demographics, systemic and radiation tx history were obtained. Diagnosis of RN was established by MRI in all pts, and pathology confirmed RN in one pt. Results: Description of the 6 pts identified are shown in Table 1. Conclusions: We present 6 melanoma pts who developed RN after CNS radiation and who were treated with 2-6 doses of Bev. None of these pts developed bleeding, and all pts experienced improvement in symptoms and quality of life, with concurrent improvement of imaging in 5 pts. Our series suggests that in selected melanoma pts Bev may be a safe and effective treatment for RN for MBM and should be evaluated in a prospective setting. [Table: see text]
ADR-201: A novel cytotoxic drug-conjugate for pancreatic cancer.
Authors: Ricigliano Mark , Cooper Brandon , Bartlett Andrew , Yu Kenneth H. 
Published: September 2018

e14018 Background:Standard of care treatment for pancreatic adenocarcinoma (PDAC) consists of FOLFIRINOX or gemcitabine with nab-paclitaxel used in either the front-line or 2nd line treatment. There is no consensus for 3rd line treatment. We previously demonstrated that Mitomycin C (M) and Cisplatin (C) as viable 3rdline treatment options with broad use limited by toxicity. To address the toxicity issues with the prolonged use of M and C, we developed a novel cytotoxic drug conjugate ADR-201 (A), as a treatment option for metastatic PDAC . Methods: (A) is a cytotoxic drug conjugate formed from the APIs of Mitomycin C (M) and Cisplatin (C) conjugated with an amine-to-sulfhydryl crosslinker with a soluble polyethylene glycol (PEG) spacer arm to reduce steric hindrance. In order to conjugate C, the molecule was thiolated prior to crosslinking with a maleimide functional group. In cytotoxic assays, MiaPaca-2 cells were treated with 17uM of A and cell viability was measured at 48hrs, 72hrs and 96hrs. In thin layer chromatography (TLC) A, M and C were spotted at the origin with 0.5uL of 17uM, 10mM and 10mM respectively. Cell cultures comprising circulating tumor and invasive cells (CTICs) obtained from PDAC patients (n = 12) were treated with 17uM of A and cell viability was measured at 72hrs. Results: In TLC, A showed marked solubility in polar neutral solvent EtOAc /hexane (20:80) compared to the polar compounds M and C with Rf values 0.38:1.0:1.0 respectively. In cytotoxic assays with MiaPaca-2 cells, serial dilutions of A at 17uM, 8.5uM and 3.4uM demonstrated a 30%, 11% and 6% reduction in cell viability at 72hrs. In 24 CTIC cultures, A reduced cell viability between treatment v control groups by an average -26%. (range -31% - 0%, paired t-test, p-value = 0.013, ). Conclusions: Improvements in solubility and cytotoxic activity at low dose levels compared to single agents M and C should translate to enhanced permeability and retention (EPR) in tumor tissue with corresponding reduced toxicity.
Evaluation of PFS ratio in patients with cancer enrolled in early-phase clinical trials: A single center, retrospective analysis.
Authors: Watson Sarah , Bonnet Clement , Menis Jessica , Michot Jean-Marie , Hollebecque Antoine , Massard Christophe , Soria Jean-Charles , Postel-Vinay Sophie , Paoletti Xavier 
Published: September 2018

e14025 Background: Progression-free survival ratio (PFSr) has been proposed as a direct evaluation of treatment benefit in advanced cancer patients, based on the hypothesis that the natural history of cancer is accelerating and therefore successive lines of treatments become less efficient over time. Consequently, PFS at line +2 (PFS2) is expected to be shorter than PFS at line +1 (PFS1), whereas a PFS2/PFS1 ratio > 1.3 might reflect treatment benefit. However, this hypothesis has been poorly documented, especially in the context of early phase trials where determining treatment benefit is becoming key. We therefore proposed to evaluate PFSr in a large cohort of cancer patients enrolled in early phase clinical trials at Gustave Roussy Drug Development Department. Methods: Patients enrolled in at least two phase 1 studies for advanced solid tumors or lymphomas were retrospectively identified. Demographical, clinical and therapeutic data were collected. Time to progression (PFS) was measured from treatment initiation to progression, using radiological evaluations. Patients who had gone off-trial for reasons other than progression were censored. PFSr was defined as the ratio of the PFS under line 2 divided by the PFS under line 1 and might be censored in presence of censored PFS2. Ratio distribution in this population was estimated using Kaplan Meier. Calibration of the ratio was proposed for hypothesis testing. The influence of therapeutic class and combination versus monotherapy was studied via non parametric Gehan-Wilcoxon tests or Mick tests. Results: 212 patients enrolled between 2009 and 2016 in at least two phase 1 clinical trials were included, corresponding to 113 different clinical trials. PFSr distribution was described and correlated with demographical, clinical and therapeutic data. The relevance of the usual 1.3 PFSr cut-off to determine treatment benefit was evaluated. Final analysis results will be presented at the time of the congress. Conclusions: This study, one of the first to establish PFSr in a large cohort of patients treated in early phase clinical trials, provides guidelines for using PFSr to assess the impact of treatment sequences in advanced cancer patients.
A phase 1/2 study of a novel IL-2 cytokine, NKTR-214, and nivolumab in patients with select locally advanced or metastatic solid tumors.
Authors: Diab Adi , Tannir Nizar M. , Bernatchez Chantale , Haymaker Cara L. , Bentebibel Salah E , Curti Brendan D. , Wong Michael K.K. , Gergel Ivan , Tagliaferri Mary Ann , Zalevsky Jonathan , Hoch Ute , Aung Sandra , Imperiale Michael , Cho Daniel C. , Tykodi Scott S. , Puzanov Igor , Kluger Harriet M. , Hurwitz Michael E. , Hwu Patrick , Sznol Mario 
Published: September 2018

e14040 Background: NKTR-214 is a CD-122-biased agonist that targets the IL-2 pathway and is designed to provide sustained signaling through the heterodimeric IL-2 receptor pathway (IL-2Rβɣ) to preferentially activate and expand NK and effector CD8+ T cells over T regulatory cells within the tumor microenvironment. In a phase 1 monotherapy trial, pts treated with NKTR-214 demonstrated a substantial increase in CD8+ T and NK cells within the tumor microenvironment even when pretreated with multiple prior immunotherapeutic agents (abstract submitted). Based on this biomarker data and a favorable safety profile, a trial combining NKTR-214 and nivolumab was initiated. Methods: This is an on-going phase 1/2 study of NKTR-214 plus nivolumab in Pts with either melanoma (Mel), NSCLC, renal, bladder, or TNBC. Pts who are immunotherapy naïve or checkpoint therapy relapse/refractory are being studied separately. NKTR-214 and nivolumab are administered IV on a q2w or q3w schedule. Cohort 1 received NKTR-214 0.006 mg/kg q3w with nivolumab 240 mg q2w. Blood and tumor tissue were collected to measure immune activation using flow cytometry, immunohistochemistry, T cell clonality and gene expression analyses. Results: As of February 7, 2017, 5 Pts have been treated with the combination and all Pts were naïve to checkpoint inhibitors. There have been no dose limiting toxicities, no drug-related or immune related grade 3-5 adverse events (TRAEs) and no Pts have discontinued treatment. The most common TRAEs were pruritis and rash. Radiographic scans were available for 2 Pts. On treatment, Pt 1 with Mel had a mixed radiographic response at 1st scan, a ~40% decrease in LDH and a robust tumor immune cell infiltrate at week 3 the majority being newly proliferating CD8+ T cells expressing PD-1. Pt 2 with Mel had an unconfirmed complete response per RECIST 1.1 after 6 weeks of treatment; follow up tumor response data will be presented. Conclusions: Preliminary data demonstrate that NKTR-214 and nivolumab combination therapy is well tolerated with early evidence of clinical activity. Updated safety, pharmacokinetics, tumor response and biomarker data will be presented. Clinical trial information: NCT02983045.
A phase I study to evaluate the pharmacokinetics of a new oncology nce, apatinib mesylate tablets, with and without food following single and multiple doses in healthy subjects.
Authors: Pesco Koplowitz Luana , Koplowitz Barry , Park Cheol Hee , McGinn Arlo N. 
Published: September 2018

e14049 Background: Apatinib Mesylate (YN968D1) is a selective inhibitor of VEGFR-2 being developed for the treatment of advanced gastric cancer. Objectives: 1. Evaluate single- and multiple-dose PKs 2. Evaluate food effect on bioavailability 3. Evaluate dose-proportionality 4. Determine CYP3A4 and 2C19 metabolic effects on the PKs Methods: Single ascending-dose (SAD), open-label, crossover of 2 oral doses of apatinib mesylate tablets (100 mg and 250 mg, [81 mg and 201 mg apatinib]) in healthy male and female volunteers with a minimum 3-day washout between dosing, plus a multiple ascending-dose (MAD), open-label, crossover study of the same doses. Both doses were administered with and without food in a crossover for the SAD and MAD parts. PK blood samples were collected for each dosing period. Subjects were genotyped for CYP3A4 and CYP2C19. WinNonlin 6.4 used for analysis. Results: 24 male and female subjects completed the SAD study section. They were extensive or intermediate metabolizers of CYP2C19, and 23/24 were normal metabolizers of CYP3A4. 22 male and female subjects completed the MAD study section. Most were extensive, intermediate or ultra-rapid metabolizers of CYP2C19; 21/22 subjects were normal metabolizers of CYP3A4. Conclusions: For the 100 mg dose in the SAD and MAD parts of the study, there was no significant food effect. For the 250 mg dose in SAD and MAD parts, food appeared to increase bioavailability by 20–30% in the SAD part, and 30–40% in the MAD part. Noncompartmental PK analysis of the SAD and MAD showed medium tmaxvalue delayed at 2 doses when apatinib was administered with food. Compartmental PK analysis showed food delayed initiation in absorption and reduced first order absorption rate constant. Dose proportionality was confirmed only for the AUC0-∞ value from the SAD-fasted cohort but inconclusive for Cmax and AUC parameters under other dosing regimens. Visual inspection of the effect of CYP2C19 genotype on the clearance of apatinib did not show correlation. Inspection of CYP3A4 genotype on the calculated clearance values was tenuous given the intermediate metabolizers (N = 1), compared to extensive metabolizers.
Results of bevacizumab biosimilar compared with RMP for the treatment of metastatic colorectal cancer.
Authors: Roca Enrique Luis , Vinnyk Yuriy , Bondarenko Igor , Shparyk Yaroslav V. , Bariani Giovanni Mendonca , Abdalla Kathia , Franke Fábio , Cruz Felipe , Romera Alvaro , Bhamare Sulabhchandra , Sudalaiandi Suresh , Ostwal Vikas S. , Shah Pradeep , Rahuman Sajeed , Cubillo Antonio , Huerga Camino , Paravisini Alexandra , Fernandez Francisco Javier , Millan Susana 
Published: September 2018

e14065 Background: BEVZ92 has being developed as a proposed biosimilar approved reference medicine product (RMP). BEVZ92 has an identical amino acid sequence and highly similar physicochemical and in vitro functional properties to RMP. The aim of this study was to demonstrate pharmacokinetics (PK) similarity of BEVZ92 to RMP, in combination in combination with FOLFOX or FOLFIRI, as first-line treatment in patients with mCRC (NCT02069704). Methods: PK analysis for multiple dose studies was conducted, as per guidelines, measuring the total exposure area under the concentration-time profile (AUC0-336) at cycle 1, and to the end of the dosing interval at steady-state (AUCss) at cycle 7. PK similarity was achieved if 90% confidence interval (CI) for the test-to-reference ratios of AUC0-336h and AUCss were within 80.00–125.00% bioequivalence acceptance window. Secondary endpoints included other PK parameters, safety profile, immunogenicity and objective response rate (ORR). Results: A total of 142 patients were randomized and treated. Bevacizumab serum concentrations showed a ratio (90% CI) of geometric means for BEVZ92 and RMP were 99.4% (90.5%-109%) and 100% (90.2%–112%) for AUC0-336h and AUCss, respectively. All secondary PK endpoints which include Cmax, Ctrough, Tmax, t1/2, Kel, CL, Vd, and RA-AUC were also similar between the two arms. The ORR was 45% (95% CI, 33% to 57%) for BEVZ92, and 52% (95% CI, 40% to 64%) for RMP. Immunogenicity results showed a low incidence in the anti-drug antibodies de novo development and similar between both arms. Safety profile in terms of nature, frequency and severity was similar to the RMP and according to what is expected given the underlying disease and concurrent use of chemotherapy. Conclusions: These study results confirm the bioequivalence of BEVZ92 and the RMP in a real and common clinical setting, and translates the high similarity demonstrated in the in vitro and in vivo characterization into the clinical outcomes such as efficacy, immunogenicity and safety profile. Clinical trial information: NCT02069704.
Combined treatment of apatinib with docetaxel in non-small-cell lung cancer mice and its material basis of pharmacokinetics.
Authors: Zhou Fang , Feng Siqi , Zhang Jingwei , Aa Jiye , Wang Guangji 
Published: September 2018

e14069 Background: Apatinib, a small-molecule inhibitor of vascular endothelial growth factor receptor-2, has attracted many attentions due to its encouraging anticancer activity in clinic third-line treatment across a broad range of malignancies, including gastric cancer, non-small-cell lung cancer (NSCLC) and colorectal cancer. Its usage in second-line with chemotherapeutic drugs is still under exploration. This study is focus on the antitumor effect of apatinib combined with docetaxel (DTX) on NSCLC and its pharmacokinetic material basis. Methods: Apatinib (150 mg/kg, every day, p.o.) with or without DTX (8 mg/kg, q3d for four times, i.p.) was administered in A549 xenograft nude mice. The antitumor effect, histopathology of important organs and serum transaminases for liver function were detected. The metabolomic changes in serum were profiled by GC/MS and analyzed for the treatment outcome. The effect of apatinib on DTX concentrations in plasma, tumor and other tissues were determined by LC-MS/MS. The expressions of multidrug resistant transporters were detected. Effects of apatinib on the uptake, efflux and subcellular distribution of DTX in A549 cell and A549/DTX (DTX resistant) cell were investigated. Results: Apatinib enhanced the antitumor effect of DTX with alleviated DTX-induced inflammatory cells infiltration in liver and decreased serum transaminases (ALT and AST). Metabolomic results showed that serum endogenic molecules of apatinib and DTX co-treatment mice were closer to that of normal nude mice when compared to the DTX group. Apatinib significantly increased DTX concentration in tumor (up to 1.82 times) without enhancement in serum, heart, liver, lung and kidney. Additionally, apatinib decreased the DTX-induced upregulation of P-glycoprotein in tumor. In vitro, apatinib increased the cell/subcellular accumulation (especially in cytosol) and decreased the efflux of DTX in A549/DTX cells, while apatinib exerted no significant effect on cellular pharmacokinetics of DTX in A549 cells. Conclusions: Apatinib has a potential application prospect in second-line therapy combined with DTX for NSCLC patients, especially for multidrug resistant patients.