bluuebunny/crossref_metadata_2025 huggingface dataset:
Temozolomide (TMZ) maintenance in patients with primary brain cancer treated with postoperative TMZ plus radiotherapy (RT): A retrospective analysis.
Authors: Moscetti Luca , Fabbri Maria Agnese , Sperduti Isabella , Mansueto Giovanni , Fariello Anna Maria , Gamucci Teresa , Battista Michle , Loffreda Massimiliano , Pompei Luciano , Ruggeri Enzo
Published: March 2020

e12514

Background: A systematic review of patients affected with primary brain cancer treated with post-operative TMZ+RT and TMZ maintenance was undertaken in order to evaluate the efficacy and toxicity in an unselected population. Methods: Ninety-nine patients were detected. Main characteristics were: median age 62 years (range 28-80); M/F: 58/41; PS 0/1: 92 pts; complete resection: 20; subtotal resection: 75, biopsy only: 4. The median RT dose delivered was 60 Gy (range 40-60 Gy). All the 99 pts received TMZ at 75 mg/m2 concomitantly to RT. Maintenance therapy with TMZ was given to non progressive pts, starting 6 weeks after chemoradiation, at the dose of 150 mg/m2 for the 1st cycle and 200 mg/m2 q 4 weeks d. 1-5 for subsequent cycles and continued until disease progression or intolerance. Results: Patients with evaluable disease (n=79 pts) had an overall response rate of 16% (12 partial response and 1 complete response), while a stable disease was observed in 49/79 pts (62%). Maintenance TMZ was given to 77/99 pts (78%). Hematologic toxicities (CTCAE v.3) include: Gr. 3/4 neutropenia (4%), febrile neutropenia (1%), Gr. 3/4 thrombocytopenia (13%), Gr. 3 anemia (1%). One pt developed a bone marrow aplasia and another one a Steven-Johnson syndrome recovered after high supportive treatment. Toxicities caused discontinuation of TMZ in 9 patients (11%). At 2-yrs, at both univariate and multivariate analysis, a significant improvement in progression-free survival (PFS) and in overall survival (OS) was observed in pts completely resected and in pts achieving a response or a stable disease >6 months. In pts achieving a response and in pts completely resected the HR for the 2-yrs PFS was 0.06 (95%CI 0.03-0.11, p<0.0001) and 0.02 (95%CI 0.01-0.04, p<0.0001), respectively. For the 2-yrs OS the HR was 0.08 (95%CI 0.04-0.16, p<0.001) and 0.02 (95%CI 0.01-0.06, p<0.0001). No difference was observed for sex, age, PS and histology. Conclusions: Complete resection, response or prolonged stabilization to maintenance TMZ are factors associated with a statistically improvement in OS and PFS.
Results of Australasian Gastrointestinal Trials Group (AGITG) Arctic study: An international audit of raltitrexed for patients with cardiac toxicity induced by fluoropyrimidines (FP).
Authors: Ransom David , Wilson Kate , Bishnoi Sarwan K. , Simes John , Yip Desmond , Karapetis Christos Stelios , Gebski Val , Gordon Stephen , Fournier Marion , Ferry David Raymond , Abbas Haider , Midgley Rachel A , Price Timothy Jay
Published: March 2020

e13007

Background: Cardiac toxicity (CT) is an uncommon but potentially fatal side effect of FP. The incidence of further CT if the same chemotherapy is continued is reported to be 20% (Jensen SA et al. Risk factors and prevention of cardiac toxicity induced by 5-fluorouracil or capecitabine. Cancer Chemotherapy & Pharm. 58:487-93, 2006). Management of these patients remains poorly defined. Treatment options include continuing same dose and schedule of FP, adding a nitrate and calcium antagonist; switching to bolus FP; or substituting with raltitrexed. Previous publications of patients experiencing CT and switching FP to raltitrexed are limited to case reports. Methods: AGITG & OCTO (Oncology Clinical Trials Office – Oxford) members identified patients who had CT from FP, and were subsequently switched to raltitrexed. CT included angina, myocardial infarct (MI) or arrhythmia. A coronary angiogram was not mandatory. Results: 38 patients were included in clinical audit. Cancer diagnoses included colorectal (35pts), cervix (1), oesophageal (1) and ampullary carcinoma (1). Median age - 61 years (range 36-81). 24 patients (63%) were male. Median number of cycles prior to switching to raltitrexed was 2 (range 1-11). FP regimens included FOLFOX, CAPOX, continuous infusion 5FU, capecitabine alone. 35 patients had angina, 6 MI, and 1 arrhythmia with some patients experiencing >1 event at that time. 7 patients experienced two separate CT events, and 2 had three events prior to switching to raltitrexed. Following CT 8 patients received raltitrexed alone, 29 received raltitrexed in combination with other agents or radiotherapy and one received raltitrexed alone followed by combination. Median number of raltitrexed cycles was 5 (range 1-21). After switching to raltitrexed 2 patients experienced another cardiac event (5.3%, 95% CI:1.5-17.3), significantly different from 20% (p=0.023), the reported rate of cardiac toxicity due to continuing FP. Conclusions: For patients who experience CT from FP switching to raltitrexed is an option with the rate of additional cardiac events lower than previously reported for continuing same FP.
13C-uracil breath test to predict 5-fluorouracil toxicity in gastrointestinal cancer patients.
Authors: Cunha Geraldo Felicio , de Marco Luiz , Bastos-Rodrigues Luciana , Bolina Marina Borges , Martins Flavia Linhares , Pianetti Gerson Antonio , Cesar Isabela Costa , Coelho Luiz Gonzaga
Published: March 2020

e13008

Background: Up to 30% of patients on 5-fluorouracil (5FU) experience severe toxicity. Dihydropyrimidine-dehydrogenase (DPD) deficiency explains 36-61% of cases. Predicting toxicity is an unmet challenge. Uracil breath test (UraBT) consists of measuring 13CO2 in exhaled breath after ingestion of 2-13C-uracil to evaluate pyrimidine (and 5FU) catabolism. Methods: We studied 33 gastrointestinal cancer patients previously exposed to 5FU: thirteen had grade 3-4 and 20, grade 0-1 toxicity. Groups were well-balanced regarding: age (median, 57 years); gender (males, 35%); primary (colorectal, 90%); ethnicity (Caucasians, 55%); chemotherapy (Mayo clinic regimen, 75%). Main toxicities were febrile neutropenia, diarrhea and stomatitis. Tests used to evaluate pyrimidine catabolism: (1) sequencing of three exons of DPYD; (2) plasma dihydrouracil/uracil ratio (UH2/U); (3) UraBT. We tested the performance of UraBT to discriminate patients who had grade 0-1 toxicity versus grade 3-4 toxicity and patients with and without proven DPD-deficiency. DPD-deficients were defined as having had grade 3-4 toxicity plus either UH2/U < 1.8 or deleterious mutation. Results: 4/13 grade 3-4 toxicity patients proved to be DPD-deficient: three had deleterious mutations (IVS14+1G>A in one; SNP 2846A>T in two), and one had low UH2/U ratio. Mean delta over baseline in 50 minutes (DOB50) significantly differed between groups. DOB50 ≤ 161.4 discriminated individuals with grade 3-4 versus grade 0-1 toxicity (sensitivity= 61.5%; specificity= 85%) and DPD-deficient versus non DPD-deficient (sensitivity= 75%; specificity= 85%). Conclusions: UraBT is a non-invasive and easy to perform method with promising accuracy in discriminating individuals with severe toxicity to 5FU, comparing favorably to most tests available to predict 5FU toxicity. [Table: see text]
Phase I safety and tolerability of once daily oral afatinib (A) in combination with docetaxel (D) in patients (pts) with relapsed or refractory advanced solid tumors.
Authors: Senellart Helene , Bennouna Jaafar , Isambert Nicolas , De-Montserrat Helene , Squiban Patrick J. , Tschoepe Inga , Delord Jean-Pierre
Published: March 2020

e13010

Background: A is an orally bioavailable, irreversible, ErbB Family Blocker. This open label, Phase I, dose escalation trial investigated the safety, tolerability, and PK of A, in two parallel dose cohort expansion parts, in combination with either gemcitabine (Part A) or D (Part B) in patients with relapsed or refractory solid tumors. Preliminary results from Part B are presented here. Methods: Eligible pts (confirmed diagnosis of advanced solid tumors, ECOG PS 0–1) received once daily, oral dosing of A in combination with D, given iv on Day 1 of every 3 week cycle. Dosing of A started on Day 2 of Cycle 1. Primary objective was to establish the maximum tolerated dose (MTD) based on the occurrence of dose limiting toxicities (DLT) observed in Cycle 1. Dose escalation was performed with cohorts of 3–6 pts using a 3+3 design. Initial starting dose level was A 30 mg/day and D 60 mg /m², escalating up to A 50 mg/day and D 75 mg/m² until the MTD was reached, and followed by a PK expansion cohort of 12 pts at the MTD level. Incidence and severity of AEs were recorded. Results: To date, 21 pts have been treated with A (30–50 mg/day) and D (60–75 mg/m2), with baseline characteristics: mean age (55.4 years), women (42.9%) and number of prior chemotherapies (≤2: 57%; >2: 43%). Fourteen pts received 2–4 cycles of treatment and five patients received 4 or more cycles. In Cycle 1, DLT was experienced by one out of six pts receiving 30 mg afatinib + 60 mg/m² docetaxel (Grade 3 diarrhea). No DLT was observed during the subsequent dose levels up to A 50 mg/day and D 75 mg/m². AEs observed in most pts were diarrhea (76.2%) and asthenia (66.7%). Conclusions: In pts with relapsed or refractory advanced solid tumors, the combination of A and D is well tolerated. AEs were manageable and the MTD was not reached in the tested dose range up to A 50 mg/day and D 75 mg/m². Considering the potential for diarrhea and rash during later cycles, the recommended dose for the expansion cohort was A 40 mg/day in combination with D 75 mg/m². Enrollment is ongoing (nine pts to date) and additional safety data and preliminary evidence of activity are anticipated to be available at the time of presentation.
Response of HER2+ breast cancer patients to allogeneic cell immunotherapy.
Authors: Har-Noy Michael , Lausoontornsiri Wirote , Or Reuven , Katsanis Emmanual
Published: March 2020

e13013

Background: The immune mechanism of non-myeloablative allogeneic stem cell transplantation has been shown to be effective in debulking chemotherapy-resistant metastatic cancer despite the presence of immunoavoidance mechanisms, but this immune effect is intimately related to GVHD toxicity limiting the clinical application. An allogeneic cell therapy (aCT) with intentionally mismatched, CD3/CD28 microbead-conjugated CD4+ memory cells exhibiting both Th1- and NK-like properties designed to elicit autologous anti-tumor effects in the context of graft rejection was evaluated in a FDA-approved phase I/II clinical trial of 42 refractory metastatic solid tumor patients with a variety of indications. No objective tumor response was observed, however there was evidence of enhanced survival and immune-mediated tumor debulking without GVHD toxicity. RECIST overestimated tumor burden, as responding tumors swelled and appeared larger on CT. Multi-parameter analysis identified serum IL-12 as a predictor of enhanced survival. 50% were IL-12+ and survived a median of 211 days vs. 131 days for IL-12- patients (p<.009). Methods: An analysis of IL-12+ responders was conducted to determine the indication with the highest IL-12 response. Results: 9 of 16 refractory metastatic breast cancer (mBC) patients were IL-12+. The Her2+ subset of mBC were 100% IL-12+ (5 of 5) with a median survival of 416 days, while the 11 Her2- patients had a median survival of only 134 days (p<0.05). Conclusions: Normally, Her2+ tumors are more aggressive and have a poorer prognosis than Her2- tumors. The enhanced response to aCT in Her2+ mBC may be due to high titers of anti-Her2 IgG1 antibodies known to be present in these patients. aCT upregulates host FcgR expression on host monocytes through a CD40L-CD40 mechanism. The FcgR bind IgG1 antibodies and mediate ADCC tumor lysis. We hypothesize that patients expressing tumor-specific IgG1 autoantibodies are more likely to respond to aCT. Serum autoantibodies to tumor-associated antigens thus may be a predictive biomarker for aCT responders. The combination of natural or exogenous tumor-specific IgG1 Abs with aCT may be a platform for refractory metastatic tumor debulking leading to increased overall survival.
Phase I trial of cancer vaccine with multiple peptides derived from novel onco-antigen and anti-angiogenic antigens for patients with advanced non-small cell lung cancer (NSCLC).
Authors: Suzuki Hiroyuki , Hasegawa Takeo , Ohsugi Jun , Hoshino Mika , Higuchi Mitsunori , Shio Yutaka , Yoshida Koji , Tsunoda Takuya , Nakamura Yusuke , Gotoh Mitsukazu
Published: March 2020

e13015

Background: Two phase I clinical trials were conducted on patients with advanced or recurrent NSCLC to evaluate the safety, immunogenicity and clinical response of a multiple peptide vaccine that incorporates four epitope peptides. This vaccine is comprised of novel HLA-A24-restricted oncoantigens, including two of the following three peptides; up-regulated lung cancer 10 (URLC10), TTK protein kinase (TTK) and cell division associated 1 (CDCA1), in addition to peptides derived from vascular endothelial growth factor receptor 1 (VEGFR1) and 2 (VEGFR2). Methods: Peptides derived from URLC10, TTK, VEGFR1 and VEGFR2 were tested in Trial 1, while peptides derived from URLC10, CDCA1, VEGFR1 and VEGFR2 were tested in Trial 2. Fifteen HLA-24-positive patients with NSCLC who had not responded to standard therapy were enrolled in this classic 3 patient per dose per cohort phase I trial, designed with varying dosages (Trial 1; 0.5mg, 1mg and 3mg, Trial 2; 1mg, 3mg). Vaccines were administered weekly by subcutaneous injection into patients’ axillary region with Montanide ISA-51 incomplete Freund’s adjuvant until progressive disease occurred and/or patients refused further treatment. Immunological responses were evaluated by INF-gamma ELiSPOT assays. Results: Vaccinations were well-tolerated withno severe treatment-associated adverse events. Specific T cell responses were induced in all patients against at least one epitope peptide. However, weak immunological responses were found in the 0.5mg group compared with the 1mg and 3mg groups in Trial 1, therefore the 0.5mg group was excluded in Trial 2. In terms of clinical responses, no complete and partial responses were found, however 9 of 15 patients (60 %) were categorized with stable disease. The median overall survival time was 13.2 months, while 1- and 2-year survival rates were 52.5% and 32.8% respectively. Conclusions: Multiple peptide vaccination therapy using four novel peptides was safe, and could possibly be effective in extending the patients’ survival. These encouraging immunological and clinical responses could provide a case for further stages of clinical trials.
Genetically engineered natural killer (NK) cell immunotherapy for children poor risk b-cell (CD20+) leukemia and lymphoma (L/L).
Authors: Chu Yaya , Ayello Janet , Hochberg Jessica , Van de ven Carmella , Murphy James , Cairo Mitchell S.
Published: March 2020

e13022

Background: A majority of children with CD20+ L/L at relapse have a chemotherapy resistant phenotype (Cairo et al Blood, 2007; JCO, 2012). Novel, non-chemotherapy-based therapies are desperately needed for this poor risk population. NK cells play an important role in tumor surveillance post allogeneic stem cell transplantation (Beziat V et al, Leukemia, 2009) but cell number and tumor recognition limit adoptive NK cell therapy (Shereck/Cairo, PBC 2007). PBNK cells expanded with genetically engineered K562-mbIL15-41BBL cells (geK562) have been previously reported (Imai C et al, Blood. 2005). Objective: We investigated the functional activities and cytolytic effect of anti-CD20 chimeric antigen receptor (CAR+) engineered PBNK cells expanded with mK562 against CD20+ L/L both in vitro and in vivo. Methods: Peripheral blood mononuclear cells (PBMC) were expanded with mitomycin C treated geK562 cells in culture medium with 10 IU/ml IL-2 for 7 or 14 days. CD56 and CD3 expression were evaluated by flow cytometry. Retrovirus preps that express CAR+ or CAR- were generated independently. The CAR+ was constructed in a MSCV-anti-CD20BB-CD3-zeta-GFP plasmid (generously supplied by Dario Campana, MD, PhD). Expanded PBMC were transduced with retroviruses as described (Imai C et al, Blood. 2005). NK cytotoxicity was assessed by europium release assay at 2:1 E:T ratio against CD20+ Ramos. Results: CD56+CD3- PBNK cells were significantly increased compared to media alone at day7 (60.94+ 3.63% vs 8.05+0.49%, n=6, p<0.001). CD56-CD3+ PBT cells were significantly reduced compared to media alone at day 7 (22.08+2.22% vs 75.73+0.75%, n=6, p<0.001). CAR+ and CAR- retrovirus supernants infected expanded PBMC at 1%-10% range. The anti-CD20 CAR expression was further confirmed by flow cytometry and western blot. We also observe that cytotoxicity was enhanced with CAR+ PBNK compared to CAR- PBNK (41+ 1.1% vs 24.5+ 3.7%) against Ramos at E:T ratio 2:1. Conclusions: PBNK can be expanded with geK562. Anti-CD20 CAR enhances PBNK anti-tumor activity against CD20+ Ramos. Future directions include characterizing the cytotoxicity activity of engineered PBNK against L/L in vitro and survival in xenogafted mice.
Cancer vaccination trial with novel multiple peptides in previously treated advanced non-small cell lung cancer.
Authors: Hirose Takashi , Noda Hidehiro , Okuda Kentaro , Abe Seiji , Oto Yuji , Kusumoto Sojiro , Sugiyama Tomohide , Ishida Hiroo , Shirai Takao , Nakashima Masanao , Yamaoka Toshimitsu , Ohmori Tohru , Yoshida Koji , Nakamura Yusuke , Adachi Mitsuru
Published: March 2020

e13029

Background: Cell division cycle associated gene 1 (CDCA1) and insulin-like growth factor-II mRNA binding protein 3 (IMP-3) are novel cancer-testis antigen overexpressed in non-small-cell lung cancer (NSCLC). The aim of this study was to evaluate the safety, efficacy, and immunological response of a novel peptide vaccination therapy, CDCA1 and IMP-3, in patients with previously treated advanced NSCLC. Methods: Human histocompatibility leukocyte (HLA)-A2402 positive advanced NSCLC patients who failed to standard therapy were enrolled if they had a performance status of 3 or less, were 80 years or younger, and had adequate organ function. The cocktail of 2 peptides was subcutaneously injected with 1 mL of incomplete Freund’s adjuvant to axillary or inguinal regions weekly. Immunological response was evaluated with enzyme-linked immunospot assay before and after vaccinations every 4 weeks. Results: From November 2009 through December 2011, 20 patients (13 men and 7 women; median age, 65 years; range, 36 to 78 years) were enrolled. CDCA1 and IMP-3 specific cytotoxic T lymphocyte responses were observed after vaccinations in 60% and 73% of patients, respectively. The overall response rate was 5% (95% CI, 0.1% to 24.9%) and stable disease rate was 55% (95% CI, 31.5% to 76.9%). The median survival time from the start of vaccination therapy was 7 months (range 1 to 26 months). The median progression free survival time was 3 months (range 1 to 15 months). One patient with interstitial lung disease (ILD) had acute exacerbation of ILD during vaccination therapy. The other 19 patients did not have any grade 3 or 4 adverse events. Conclusions: This vaccination therapy was effective and well tolerated in patients with NSCLC who failed to standard therapy, and therefore warrants further clinical studies.
Is vinorelbine pharmacokinetics modified in Asian patients when compared to caucasian patients?
Authors: Ferre Pierre , Shao Zhimin , Jiang Zefei , Zhong Dafang , Xiaoyan Chen , Burillon Jean-Philippe , Petain Aurélie , Zorza Grégoire , Zhang Li
Published: March 2020

e13036

Background: Pharmacokinetics (PK) of vinorelbine (VRL) has been extensively studied through a series of clinical studies, mainly conducted in Caucasian patients. Interethnic differences in drug disposition may however induce interethnic variation in drug exposure. Consequently, the PK of VRL was assessed in Asian patients during two clinical studies conducted in China, and compared to previous knowledge from non-Asian patients. Methods: Two phase II studies were conducted in China using VRL on Day 1 and 8 in combination on Day 1 with iv cisplatin for lung cancer (NSCLC) or with epirubicin for breast cancer (ABC). Patients were randomized within each study to receive either iv VRL (25 mg/m2 on cycle 1) or oral VRL. PK samples were obtained from subgroups of patients, and blood VRL and its active metabolite DVRL were quantified through LC-MS/MS. Bayesian PK parameters were calculated and VRL monotherapy results (iv 25 mg/m²; oral 60 mg/m²) were compared to historical single agent data from Caucasian patients. A population PK analysis (Variol P. et al. Eur J Clin Pharmacol, 2002: 58) was conducted to investigate for a potential effect of ethnicity. Results: VRL PK was evaluated in 38 NSCLC and 43 ABC Asian patients. Blood VRL and DVRL concentrations profiles were consistent with those from European studies. In Asian patients, mean Cltot/F (oral VRL) was 138 ± 56.5 and 179 ± 87.3 L/h for NSCLC and ABC, and mean Cltot (iv VRL) was 34.6 ± 8.82 and 41.2 ± 13.5 L/h for NSCLC and ABC. Those results did not differ from a reference European study (Bourgeois H. et al. Cancer Chemother Pharmacol, 2007: 60) (n = 48), for which mean clearance was 144 ± 66.6 and 42.8 ± 12.2 L/h for oral and iv VRL. The population PK analysis (n = 222 and 111 patients for oral and iv route) did not evidence ethnicity as a significant covariate on both clearance and oral bioavailability. Conclusions: The PK results reported from 81 Asian patients having received iv or oral monotherapy VRL treatment are consistent with previous data from European PK studies. This is in line with the metabolism knowledge of VRL, mainly involving esterase and CYP3A4 enzymes, which are not described as highly functionally polymorphic in Caucasian and Asian population.
A phase I study of oral darinaparsin in patients (pts) with advanced solid tumors (AST).
Authors: Camacho Luis H. , Senzer Neil N. , Harb Wael A. , Barrett John A , Korth Christopher Charles , Astl Dorothea , Jac Jaroslaw , Youssoufian Hagop
Published: March 2020

e13040

Background: Darinaparsin [Zinapar, ZIO-101(S-dimethylarsino-glutathione)], is a novel organic arsenic compound with in vitro and in vivo anticancer activity in tumor cell lines resistant to arsenic trioxide. An oral formulation is now available. Methods: This study used a 3+3 escalating design, dosing orally for 21 days followed by 7 days off (28 day cycle). Pts with AST refractory to standard therapy, ECOG performance score (PS) ≤ 2 and adequate organ function were treated. Study objectives were safety profile evaluation, pharmacokinetics (PK) and preliminary activity of oral darinaparsin. CTCAE v. 4.0 and RECIST 1.1 were used. Results: A total of 10 pts (8 males, 2 females), with ECOG PS 0=2, 1=8, mean age of 71 years (range: 60-81), median of prior therapies 3 (range: 1-4) were treated. A median of 2 cycles of darinaparsin was administered (range: 1-6). Dose limiting toxicities (DLT) were confusion (n=1; 400 mg), cognitive disturbance (n=1; 400 mg) and encephalopathic syndrome (n=1; 300 mg), reversible with drug discontinuation. The highest tolerable dose was 300 mg per day. Most frequent AEs were: hypokalemia, nausea (40% each), fatigue (30%), anemia, diarrhea, hypophosphatemia, pneumonia, vomiting (20% each). Most frequent grade ≥3 AEs were: hypokalemia, hypophosphatemia (20% each). Best overall response was stable disease (at 2 cycles), observed in 5 pts: adenocarcinoma of colon (2 pts), chordoma, adenocarcinoma of small bowel and carcinoma of tongue. PK analysis of 400 mg cohort (n=4) and 300 mg cohort (n=6) resulted in Tmax at 9 hr post treatment and Cmax slightly greater than dose proportional (p<0.05). Steady-state trough levels were achieved on or before Day 5. Approximately 40 % greater Cmax was observed on D15 compared to D1 for the 300 mg cohort (p<0.05) while unchanged at 400 mg. DLTs were observed when duration of exposure was more than 7 days and serum trough levels were 800 ng/ml or above. Conclusions: Oral darinaparsin is well tolerated at the dosage of 300 mg per day for 21days in a 28 day cycle in pts with AST. Preliminary evidence of clinical activity and a predictable PK profile justify further evaluation of darinaparsin in selected indications.
Lack of association of genetic variations of deoxycytidine kinase with toxicity or survival of non-small cell lung cancer patients treated with gemcitabine plus cisplatin.
Authors: Ryu Jeong Seon , Shin Eun Soon , Kim Hyun-Jung , Nam Hae-Seong , Lee Jong-Eun , Lim Joo Han
Published: March 2020

e13065

Background: To determine whether tagging polymorphisms (tSNPs) of deoxycytidine kinase (DCK) have an effect on toxicity or prognosis in patients with non–small-cell lung cancer (NSCLC) treated with gemcitabine plus cisplatin. Methods: Three tSNPs (−201 C>T, rs2306744; IVS2+9846 G>A, rs12648166; IVS6+1392 T>C, rs4694362) were chosen using two databases, the international HapMap Project and Japanese Single-Nucleotide Polymorphisms. Genotyping was performed using the Genome Lab SNPstream Genotyping System and SNaPShot assay kit. We evaluated the associations of the tSNPs with hematologic toxicity or overall survival of 139 NSCLC patients at stages IIIA/IIIB (59) and IV (80). Results: The median survival time of the patients was 11.9 months. Hematologic toxicity such as neutropenia, thrombocytopenia and anemia were not different by the three tSNPs or haplotypes (CGT, CAT and CAC) of DCK. The genetic variations did not affect on survival of the patients (log-rank P: 0.248 for −201 C>T, 0.571 for IVS2+9846 G>A, 0.686 for IVS6+1392 T>C, 0,556 for CGT, 0.453 for CAT and 0.845 for CAC). In Cox model, these tSNPs and haplotypes did not reveal prognostic relevance (aHR and 95%CI: 0.954 and 0.611 to 1.489 for −201 C>T; 1.193 and 0.719 to 1.979 for IVS2+9846 G>A; 1.072 and 0.674 to 1.706 for IVS6+1392 T>C, 0,668 and 0.205 to 2.175 for CGT, 1.043 and 0.713 to 1.525 for CAT and1.043 and 0.701 to 1.550 for CAC). Conclusions: This is the first study to focus on the association of tSNPs and their haplotypes of DCK with toxicity and survival in NSCLC patients. This suggests that genetic variations of DCK have no effect on the outcomes in the patients treated with gemcitabine-based chemotherapy.
In situ distribution of metallic platinum in tumor tissues after intraperitoneal platinum chemotherapy assessed by digital synchrotron-abetted x-ray fluorescence microscopy.
Authors: Taub Robert N. , Leinwand Joshua , Bates Gleneara , Hare Elethea , Borczuk Alain C. , Graziano Joseph , Lanzirotti Antonio , Miller Lisa
Published: March 2020

e13067

Background: Hyperthermic intraoperative intraperitoneal chemotherapy (HIPEC) and catheter-administered intraperitoneal chemotherapy (CAIPEC) are used to treat peritoneal surface-spreading malignancies, including Malignant Peritoneal Mesothelioma (MPM), to maximize local drug concentrations. Previous HIPEC studies showed tissue penetration of cisplatin ~5mm from the peritoneal surface; biodistribution of CAIPEC has not been reported. Methods: Our protocol for MPM includes initial debulking surgery with HIPEC (41°C over 1 hour, drug is then removed), 6 cycles of CAIPEC (room temperature, indefinite dwell-time), and a second debulking surgery with HIPEC. To compare tissue drug penetrations in HIPEC versus CAIPEC, on an IRB-approved protocol we collected peritoneal tissue from 6 MPM patients receiving HIPEC at initial (n=2; both cisplatin) or second surgery (n=4; 2 cisplatin and 2 oxaliplatin) for digital image localization of in situ Pt by synchrotron-abetted (Brookhaven National Laboratory, Upton NY) x-ray fluorescence microscopy at a resolution of 10 microns. Results: Overall Pt levels were highest at second surgery post-HIPEC (median=26.1ppm, range: 2.2-113.4), lowest at initial surgery post-HIPEC (median=5.2ppm, range=4.7-5.8), and intermediate at second surgery pre-HIPEC (median=16.0ppm, range=5.6-21.8). Every sample had higher Pt at the peritoneal surface; also highest at second surgery post-HIPEC (median=40.4ppm, range=4.4-219.7), lowest at initial surgery post-HIPEC (median=11.3ppm, range=8.4-14.2), and intermediate at second surgery pre-HIPEC (median=25.9ppm, range=8.4-29.9). At second surgery, each sample’s overall Pt level was higher than contemporaneous plasma Pt, pre-HIPEC (median=0.27ppm, range=0.08-0.33) and post-HIPEC (median=1.86ppm, range=0.84-2.87). Conclusions: Both CAIPEC and HIPEC effect tissue drug accumulation, greatest at the peritoneal surface. The proportion of peritoneal surface Pt was lowest in second surgery pre-HIPEC samples, suggesting more homogeneous and/or extensive drug distribution in CAIPEC than HIPEC, likely due to longer dwell-time.
Analyzing changes in oncology trial records over time using automated semantic web-mining.
Authors: Cocker David J , Lievens Johanna Caroline , Geentjens Kristof , Van Remortel Piet , De Cre Mireille , Naudts Bart
Published: March 2020

e13073

Background: Incorrect assumptions and poor feasibility are often cited as the major cause of study delay and outcome resolution. Trial placement and recruitment can be optimized by monitoring and regular assessment of trial registries. However, just a snapshot analysis does not take into account retrospective editing of records. This paper evaluates the effectiveness of a robotic, semantic analysis of registered oncology trials to assess individual changes in trial records over time. Methods: Evaluating individual trial records from 2008 to 2012 with state-of-the art natural language processing and semantic linking of data fields within clinical trial registries and literature databases to add increased resolution to erroneous or inadequate registry fields. Results: Substantial modifications are made to registration records over the life cycle of a clinical trial. Quantifiable fields as recruitment, site numbers and end dates all deviate significantly from the study roll-out. Analysis of oncology trials recruiting over 200 patients between 2008 and 2012 shows two thirds of trials deviate from the initial record. Most frequently study end date is delayed (about 50% of all trials) or enrollment targets are amended (at least 25%). Over all oncology indications, enrollment increases are twice more frequent as decreases. However, there are notable exceptions such as lung cancer, where enrollment is frequently decreased. A differential analysis of countries and sites in commercial oncology phase III trials over the period revealed a marked shift of research to sites in France, Spain, the UK and China. However, when sites were added to ongoing trials this general trend was not entirely followed as Poland, Japan, Belgium, Argentina and Switzerland were frequently chosen as additional countries above the normal distribution, suggesting these are preferred countries for trial “rescue”. Conclusions: This paper demonstrates the effectiveness of automated semantic web-mining to identify incorrect clinical trial assumptions and subsequent remediation.
Pharmacokinetics of samarium-153-EDTMP (153Sm) prior to and following zoledronic acid (ZA) in prostate cancer (PC) patients with bone metastases (BM).
Authors: Bauer Kenneth S , Tavakkoli Fatemeh , Bazzi Mouhamad , Molchanova-Cook Olga , Chen Wengen , Hussain Arif
Published: March 2020

e13075

Background: 153Sm and ZA are often employed to manage complications related to BM. Although 153Sm and ZA bind to overlapping sites within the bone, there is a paucity of information on potential pharmacokinetic (PK) and pharmacodynamic interactions between the two. In this study we report the pharmacokinetics of 153Sm when administered in combination with ZA. Methods: The study was carried out as two independent phase I trials assessing the effects of escalating dose 153Sm (0.5, 0.75, 1.0, and 1.25 µCi/kg) administered prior to or immediately after intravenous ZA 4 mg. Study 1 recruited 12 ZA-naive PC pts, while Study 2 enrolled 10 PC pts who had received at least 3 months of ZA prior to trial entry. On study, pts received 2 doses of 153Sm given 3 months apart and 6 doses of ZA given monthly. In Cycle 1 of both trials, 153Sm was administered on day1 and ZA on day 2. In Cycle 2, ZA was administered 1 hour prior to 153Sm on the same day. Blood samples for radioactive analysis were obtained at 5 min, and 0.5, 1, 2, 4, and 24 h post 153Sm dosing. PK analysis was performed by both model independent and PK modeling methods using WinNonlin. Results: The PK parameters of 153 Sm were highly variable between patients. The coefficient of variation of the Cmax/Dose was greater than 50% in all subgroups. A dose related increase in exposure to 153Sm was observed with high variability as well. The estimated terminal half-life (t1/2) was similar across all dose levels within each study. The t1/2 for Cycle 1 was 4.73 ± 1.27 for Study 1 and 6.73 ± 3.92 h for Study 2. The dose normalized Cmax (Cmax/Dose) was 0.068 ± 0.036 and 0.061 ± 0.043 µCi/mL for Study 1 and Study 2, respectively. Pharmacokinetic parameters for Cycle 2 were similar to those calculated for Cycle 1 within each study. Conclusions: The Cmax and t1/2 reported here are similar to previous studies of 153Sm with doses ranging from 1.0 to 3.0 µCi/kg in ZA-untreated pts. Although not statistically significant, the subtle differences in the pharmacokinetics of 153Sm merit further investigation.
Retrospective safety assessment of bendamustine in patients with renal impairment.
Authors: Nordstrom Beth L , Knopf Kevin B. , Teltsch Dana , Engle Robert , Beygi Hooman , Sterchele James A.
Published: March 2020

e13081

Background: Patients with non-Hodgkin’s lymphoma (NHL) and chronic lymphocytic leukemia (CLL) are at risk for renal impairment as the median age at diagnosis is >65 years. Bendamustine is a bifunctional alkylating agent with efficacy via several pathways and a manageable toxicity profile in NHL and CLL. There has been no published research on its safety in renally impaired NHL and CLL patients. Methods: In this retrospective study of 2 electronic medical record databases from US outpatient oncology practices, patients with NHL and CLL who had received ≥1 dose of bendamustine alone or with rituximab were identified and divided into investigator-defined subgroups: nonrenally impaired (creatinine clearance [CrCL] ≥40 or ≥60 mL/min) and renally impaired (CrCL <40 mL/min). Patients who received drugs with >5% risk of causing renal damage (eg, cisplatin, cyclosporine) were excluded. The study’s primary aim was to evaluate laboratory toxicities in the NHL and CLL groups. Results: Of 379 CLL patients, 42 had CrCL <40, 144 had CrCL ≥40-60, and 193 CrCL ≥60 mL/min; of 561 NHL patients, 62 had CrCL <40, 153 had CrCL ≥40-60, and 346 had CrCL ≥60 mL/min. Baseline characteristics were similar, except for more advanced age, shorter mean disease duration, and a slightly lower initial bendamustine dose in renally impaired patients. Mean total bendamustine exposure was 12 weeks for renally impaired vs 15 weeks for nonrenally impaired CLL patients, and ~16 weeks for both NHL groups. No statistically significant differences in laboratory toxicities were seen among the CLL groups, but renally impaired NHL patients had an increased risk for grade 3/4 thrombocytopenia (Cox hazard ratio [HR]: 2.57; 95% CI: 1.13, 5.85) vs those with CrCL ≥60 mL/min. In combined CLL and NHL groups, only grade 3/4 BUN increase was significantly higher for renally impaired patients vs those with CrCL ≥40 mL/min (HR: 2.36; 95% CI: 1.15, 4.86) or ≥60 mL/min (HR: 4.46; 95% CI: 1.79, 11.14). Conclusions: Though sample size and time of exposure limit the power of this study, the results support the safety of bendamustine in renally impaired NHL and CLL patients. Monitoring blood counts and renal function is probably prudent. Support: Teva Pharmaceutical Industries Ltd., Frazer, PA.
Adjudication rate as an indicator of read quality in clinical trials using progression-related endpoints assessed by imaging.
Authors: Raunig David , Goldmacher Gregory V. , Conklin James J
Published: March 2020

e13082

Background: Progression-free survival determined by serial tumor burden assessments is a common oncology trial endpoint. Images are often assessed by two reviewers, with disagreement on progression date resolved by an adjudicator. Adjudication rate (AR) is a widely used metric of read quality, with AR > 40% thought to indicate poor data. We examined factors that determine AR and the potential impact of overreliance upon it as a measure of data quality, using a statistical model of independent blinded review. Methods: Reads were simulated as a binary series of progression assessments with an underlying Gaussian decision process. Tumor burden increased in a linear fashion, with true progression at 21 weeks. Tumor measurement variability was constant, while visit frequency varied from 2 to 16 weeks. 1,000 runs of 100 patients were performed. For each run, AR and the variance and bias of time to progression were computed. Results: See table. Decreasing the visit interval relative to the progression rate increased AR but increased the accuracy and precision of the time to progression estimate. AR was less sensitive than other statistical tests of asymmetry for detection of reader bias. Conclusions: AR is affected by biological, image, and reader variability, progression rate, and visit interval. Frequent visits relative to progression increase AR, but lower bias and variance in time to progression estimates. High AR may occur even with strong readers, while very low AR may indicate loss of reader independence and data integrity. High ARs should be investigated to determine the effect on the progression endpoint. AR is not itself an endpoint, and is not a reliable indicator of read quality. Blindly attempting to minimize AR without understanding the cause may waste resources, divert attention from critical factors such as bias, and decrease a trial’s ability to detect differences between treatment arms. Other reader metrics, such as measures of asymmetrical disagreement, are recommended as alternative measures of read quality for oncology trials. [Table: see text]
Phase I clinical trial of temsirolimus (T) and vinorelbine (V) in advanced solid tumors.
Authors: Lee Grace Lauren , Ji Lingyun , Gitlitz Barbara Jennifer , Dorff Tanya B. , Iqbal Syma , El-Khoueiry Anthony B. , Roman Lynda , Edwards Susan , Menendez Xiomara , Cheng Phillip , Quinn David I. , Cole Sarah , Garcia Agustin
Published: March 2020

e13084

Background: T, an mTOR inhibitor that regulates a signaling cascade which controls growth factor-induced cell proliferation was combined with V, an anti-mitotic drug in a phase I study. Synergistic effects have been reported with this combination. The primary objective was to determine the maximum tolerated dose (MTD). Secondary objectives were to evaluate safety and tolerability. Methods: Eligible pts had advanced solid tumors, performance status 0-2, adequate organ function, and signed consent. Pts were treated with escalating doses of T and V. A 3+3 design was used. 4 dose levels were planned: Level I (T 20mg + V 20 mg/m2), Level II (T 25 + V 20), Level III (T 25 + V 25) and Level IV (T 25 + V 30). T was administered IV on days 1, 8, 15, and 22 while V was administered IV on days 1 and 15. Cycles were repeated every 28 days. MTD was defined as the highest dose tested in which fewer than 33% of pts experienced dose-limiting toxicity (DLT). DLTs included grade 3-4 non-hematologic toxicity (excluding inadequately treated nausea, vomiting, diarrhea, alopecia, myalgia, fatigue), hyperglycemia, hypertriglyceridemia, and grade 4 neutropenia or thrombocytopenia lasting more than 7 days. Results: Nineteen pts were enrolled (10 female, 9 male, median age 62 (35-79)), tumor types: lung (5), bladder (2), endometrial (7), prostate (2), neuroendocrine (1), vagina (2) and received a total of 50 cycles. All pts had received prior chemotherapy. Six pts were inevaluable and replaced (1 disease progression, 4 missed doses, 1 withdrew consent). Four pts were enrolled at dose level I, 9 to dose level II and 6 to dose level III. There was 1 DLT at level II (1 pt with grade 3 anorexia and dehydration) and 2 at level III (1 pt grade 3 hypokalemia; 1 pt grade 4 neutropenia). Two pts died on dose level III (1 not study related, disease progression; 1 study related, grade 4 neutropenia). Grade 3/4 toxicities were anemia (2), edema (1), hyperglycemia (1), anorexia (1), dehydration (1), hypertriglyceridemia (1), hypokalemia (2), and neutropenia (1). Dose level II was the MTD. One pt had a partial response (prostate), 6 stable disease. Conclusions: The recommended phase II dose of T + V is T 25mg and V 20mg/m2. At this dose, treatment was well tolerated.
Treatment of liver cancer by nanomedicine.
Authors: Wagner Wolfgang , Krukemeyer Manfred Georg
Published: March 2020

e13091

Background: Oncological surgery as a therapy branch of general surgery is registering a rapid development in the form of neoadjuvant treatment. Therapies of liver tumors display diverse treatment alternatives. Methods: The administration of cytostatics coupled with and without iron oxides (Fe3O4) has been presented in an experimental series with 36 animals with prior implantation of an R1H rhabdomyosarcoma in the liver, since iron undergoes selective phagocytosis in the liver. In Group I, mitoxantrone is injected into the lateral tail vein of the animals (n = 12) in a dosage of 1 mg/kg of body weight. Group III (n = 12 animals) received mitoxantrone coupled with iron oxide (Fe3O4), and Group II (n = 12 animals) received NaCl, in the same dosage for all groups. In the sonography and in the measurement of the volume, a significantly smaller tumor growth is found in Group II compared with Group I and III. The volume was measured manually postmortally in mm3(length x breadth x height). Results: The tumor volume showed the lowest growth in Group II, which was treated with mitoxantrone-coupled iron oxides. 3 animals from Group II died. The autopsy revealed no indication of the cause of death. There were neither thromboses nor allergic reactions in any of the animals. It can be clearly seen that Group I has a smaller mean volume and less scatter than Group II. The mean of Group I is also below that of Group II. Conclusions: It has been possible to demonstrate in animal studies that mitoxantrone-coupled iron oxide (Fe3O4) reduces the tumor volume in the liver to a greater extent that administration solely of mitoxantrone. The studies should be verified in a clinical study on humans.
Pattern of chemotherapy dosing in obese patients in a community hospital.
Authors: Thwin Malar , Soe Aye Min , Tun Nay Min , Villani Gina M.
Published: March 2020

e13099

Background: Obesity has increased to epidemic proportions, with 32.2% of US adults aged 20 years or older classified as obese (body mass index ≥ 30 mg/m2). In view of altered pharmacokinetics and possible excessive toxicity in obese patients, chemotherapy dose reductions are often employed in treating obese cancer patients. To our knowledge, there are no reports in the literature identifying patients who should have empiric dose adjustment because of obesity or the best method of dosing chemotherapy to standardize drug exposure in patients with varying degrees of obesity. As practice varies among institutions, we carried out a retrospective study to evaluate the chemotherapy dosing pattern in our obese patient population. Methods: Charts of patients who received chemotherapy at our institution during the year 2010 were reviewed. Data on age, height, weight, type and stage of cancer, date of chemotherapy, and type and dose of chemotherapy were retrieved from chart review. Only details of the first chemotherapy cycle at our institution were collected. Body surface area (BSA) was calculated by using the Mosteller formula. Independent samples t-test and Pearson chi-square statistics were used to investigate the difference between the means and proportions respectively. Results: Data from 191 patients were analyzed. Distributions (mean and range) of age, height, weight, body mass index (BMI) and BSA were 60 years (26 - 88), 65 inches (53 - 79), 166 pounds (90 - 340), 27.44 kg/m2 (14.52 - 56.57) and 1.85 m2 (1.36 - 2.66), respectively. Patients who had a full dose (n = 164) had a mean BMI of 27 kg/m2 (standard deviation (SD) 6.5) and a mean BSA of 1.82 m2 (SD 0.24) whereas those with a reduced dose had BMI (n = 27, mean 30.2, SD 7.1) and BSA (mean 1.97, SD 0.25). There is a significant difference between the means of the two groups (full dose and reduced dose) in terms of both BSA and BMI (p = 0.033 and p = 0.01, respectively). Significantly higher proportion of patients with BSA ≥ 2 received reduced dose compared to those with BSA < 2 (14 out of 48 (20.3%) versus 13 out of 143 (9%), p = 0.001). Conclusions: Patients with BSA ≥ 2 were more likely to get empiric chemotherapy dose adjustment at our institution. Further studies on chemotherapy dosing in obese patients are warranted.
Effect of VAL-083, a novel N7 alkylating agent, on growth of temolozomide-resistant primary adult glioblastoma multiforme (GBM) cells providing a new potential treatment option for GBM.
Authors: Dunn Sandra E. , Hu Kaiji , Fotovati Abbas , Chen James , Triscott Joanna , Bacha Jeffrey A. , Brown Dennis , Toyota Brian
Published: March 2020

e13123

Background: Glioblastoma (GBM) remains one of the most difficult tumors to treat first because many new agents fail to cross the blood brain barrier (BBB), and second due to intrinsic drug resistance. Temozolomide (TMZ) is a front-line therapy for the treatment of GBM; however, it is often ineffective due to drug inactivation by O6-methylguanine-DNA methyltransferase (MGMT). Cancer stem cells (CSC) are a subpopulation of the tumor that resist therapy and give rise to relapse. Here we describe VAL-083, a novel alkylating agent that creates N7 methylation on DNA, and readily crosses the BBB. VAL-083 is currently undergoing human clinical trials in the USA in refractory GBM patients. We previously described how VAL-083 can overcome resistance associated with MGMT in cell lines, and targets brain tumor CSCs. This demonstrates that VAL-083 has the potential to surpass the standard-of-care. Methods: To provide further preclinical support for VAL-083 we examined the effect of VAL-083 on primary adult GBM cells in culture, isolated fresh following surgical resection, in cases where clinical activity of TMZ was known to be limited and high expression of MGMT had been observed. Results: VAL-083 (5uM) inhibited cell growth in these primary adult GBMs that did not show significant sensitivity to TMZ in vitro. VAL-083 also inhibited the growth of CSCs by 100% in neurosphere growth assays. Conclusions: In summary, VAL-083 demonstrates in vitro efficacy against primary adult GBM cells where TMZ has limited activity thereby further supporting the potential of VAL-083 to surpas the standard-of-care.