bluuebunny/crossref_metadata_2025_split huggingface dataset:
A phase Ib dose escalation study of JX-594 (TK-vaccinia virus expressing GM-CSF) administered by biweekly intravenous infusion in patients with metastatic, refractory colorectal carcinoma.
Authors: Park Young Suk , Lee Jeeyun , Lim Ho Yeong , Lee Jihye , Pelusio Adina , Burke James M. , Breitbach Caroline , Kirn David H. 
Published: March 2020

e13044 Background: JX-594 is a recombinant vaccinia virus engineered to selectively replicate in and destroy cancer cells while stimulating a systemic anti-tumor immune response and inducing a reduction in tumor blood perfusion. Preclinical data has demonstrated JX-594 activity is enhanced in cells with up regulation of the EGFR pathway. JX-594 anti-tumor activity in multiple advanced solid tumors has been observed in early stage clinical studies. This study was designed to assess the safety, MTD/MFD, and initial anti-tumor activity of JX-594 administered IV every other week x 4 total treatments in patients with metastatic CRC after failure of standard chemotherapy. Methods: A standard 3+3 dose escalation design was used to enroll patients into three dose levels (106, 107 or 3x107pfu/kg) of JX-594 administered IV every 2 weeks x4. Safety was assessed using CTCAEv3.0. Anti-tumor activity was determined based on serial CT scans and CEA measurements. Patient samples were collected for pharmacokinetics and pharmacodynamics. Results: Enrollment is ongoing with 8 patients treated at total doses ranging from 5x107 to 2x109 pfu. Adverse events have generally been limited to grade 1/2, transient flu-like symptoms (fever, chills, headache). No DLT was reported. Three patients in the top two dose levels demonstrated SD on week 4 CT scan with one maintained at week 8. In these same 3 patients, CEA declined by 50% in a single patient while the other 2 had no significant change in CEA. Conclusions: Preliminary data for this dose escalation trial demonstrates JX-594 is well tolerated after 4 IV treatments administered every other week. CEA and CT scan assessment suggest possible efficacy. Enrollment continues and an expansion cohort at the MTD is planned. Updated data is expected at the time of presentation.
Autologous dendritic cell vaccine (ADCV) in combination with plasmapheresis (PP) and cyclophosphamide (Cy) in patients with disseminated melanoma: A phase II study.
Authors: Moiseyenko Vladimir , Baldueva Irina Alexandrovma , Novik Alexey Viktorovich , Nehaeva Tatyana Leonidovna , Danilova Anna Borisovna , Danilov Alexey Olegovich , Petrova Tatyana , Protsenko Svetlana , Michailichenko Tatyana , Semenova Anna Igorevna , Teletaeva Gulfiya Midhatovna 
Published: March 2020

e13059 Background: Low immunogenicity of tumor-associated antigens, cellular and humoral immunosuppressive factors compromise adequate antitumor immune response development. We hypothesized that ADTV, PP and Cy can overcome these immune escape mechanisms by enhancing antigen presentation, suppressing T-regs and removal of various immunosuppressive substances, respectively (Nand S, 1997; Salem M, 2010). Methods: Ten pts (median age 47.3 (24-74)) with stage IV morphologically verified malignant melanoma were included in the study in 2010. All pts signed inform consent form, previously received systemic therapy and have no brain metastases. Pts received 3 procedures of middle-volume PP (removal of 10 ml/kg plasma) on days 1,3,5 of the first 4 cycles, Cy 300 mg IM on day 5 after PP, DCV in 4 intradermal injection of 5-20*106 mature DC on day 8 of 14-day cycle. Pts with no evidence of disease progression after 4 cycles received Cy and DCV without PP once in a month for 1 year and once in 3 month thereafter until disease progression. Primary endpoint was Progression Free Survival (PFS). Secondary endpoints were toxicity (per CTCAE), efficacy (per irRECIST) and immune response using ELISpot and whole cell Elisa tests. Median of patient’s observation was 231 days. Results: Ten pts received 73 (2-21) cycles of therapy. No gr. 4 AE or SAE occurred. One patient (1.4% of cycles) developed gr. 3 fever. Main gr. 1-2 toxicities were fever (34.2%), flu-like syndrome (17,8%) and PP-related reactions, such as citrate intoxication, nausea or hypotension (16,4%). One pt achieved PR (10%, 95% CI 0 - 35%) lasting 956+ days. Four pts (40%, 95% CI 13-70%) had SD for 168, 262, 417 and 454 days (3/4-stage M1c). Median PFS was 168 (95% CI 10-325) days. IFN-γ production increased in all patients irrespective of tumor response (p=0.017). All patients with clinical benefit showed increased production of tumor-specific IgG in whole cell ELYSA. Relative risk of disease progression was 6.0 (95% CI 1.003-35.9, p=0.023) in the absence of tumor-specific IgG production. Conclusions: ADCV with PP and C is well tolerated and shows significant immunological and clinical response in pretreated stage IV pts.
Quantitative contrast peritoneography for intraperitoneal chemotherapy.
Authors: Leinwand Joshua , Guo Xiaotao , Krishnamoorthy Saravanan , Qi Jing , Hare Elethea , Schwartz Lawrence H. , Zhao Binsheng , Taub Robert N. 
Published: March 2020

e13064 Background: Catheter-administered intraperitoneal (IP) chemotherapy is used for peritoneal surface-spreading malignancies to maximize local drug concentrations. Computed tomography (CT) peritoneography can be used to assess for catheter failure and infusate maldistribution, which may contribute to treatment failure and systemic toxicities like cisplatin-induced nephrotoxicity. There is no standard system to assess infusate distribution, and no reported outcomes data from patients assessed with CT peritoneography. We hypothesized that volume and surface area of the compartment available to IP chemotherapy is associated with overall survival and post-treatment estimated glomerular filtration rate (eGFR) in malignant peritoneal mesothelioma (MPM) patients. Methods: Chart review identified 38 MPM patients who underwent CT peritoneograms while receiving IP cisplatin between 2000 and 2011. Volume and surface area of the contrast-filled compartments were calculated by semiautomated computer algorithm supervised by a physician. We retrospectively tested whether surface area and volume were associated with overall survival and post-treatment eGFR, controlling for demographic and disease factors. Results: Larger surface areas were associated with decreased likelihood of mortality, controlling for volume, age, sex and histologic subtype (Hazard Ratio=.999 cm-2, p=.035). Larger volumes correlated with higher post-treatment eGFR, controlling for pre-treatment eGFR, body surface area (BSA), surface area and the interaction between BSA and volume (β=.154 cc/min/cm3, p=.017). Conclusions: The association of larger surface areas with improved overall survival is consistent with more direct drug contact with potential areas of tumor spread. The association of larger volumes with higher post-treatment eGFR is consistent with less cisplatin diffusion into the circulation due to lower intra-abdominal pressures, which vary inversely with volume. CT peritoneography is an appropriate modality to assess distribution of catheter-administered intraperitoneal chemotherapy. Quantitative analysis of contrast-filled compartment surface area and volume may be predictive of treatment efficacy and side effects.
Role of gemcitabine along with dendritic cell therapy in advanced-stage pancreatic cancers: Phase I/II trial results in 26 patients from India.
Authors: Khan Jamal Anono 
Published: March 2020

e13071^ Background: Pancreatic cancer is the leading cause of cancer deaths worldwide with a very poor survival rate. No adequate therapy allows the patient to have a longer life of even 1 year. Methods: Dendritic cell(DC) based immunotherapy along with gemcitabine chemotherapy is planned to do phase I/II trial in 26 patients of advanced stage adenocarcinoma of pancreas. Inclusion criteria was defined as unresectable disease, ECOG performance status of not more than 2, Blood chemistry and hematocrit within normal range and of all age groups. Peripheral blood mononuclear cells are cultured in GM-CSF/IL-4 in RPMI. At 6th day of culture, the immature dendritic cells are exposed to antigens previously isolated from fresh excised tissue and further matured for 2 days. The cells along with medium are harvested and 1 million mature DC are infused IV by mixing them in 100 ml of dextrose normal saline with ondasnetron 4mg injection. Gemcitabine was given on day 1 and on day 8th and DC on day 15th. The cycle is repeated every month for 3 months followed by DC therapy alone at every 23 days interval till patient survives. The primary end point was overall survival and the secondary end point was improvement in quality quotient. Results: 6 patients survived for 24 months, 10 for 12 months and 3 for 6 months, with radiological improvement in only 4 patients with 25% reduction of disease. The quality quotient of 14 patients improved by second dose of dc therapy with improved appetite and decreased pain in abdomen including cheerfulness in 13 patients. Conclusions: Gemcitabine and DC immunotherapy is a good option for advanced stage pancreas cancer patients.
Ophthalmic acid in plasma: A possible predictor for elevated risk of erlotinib-induced hepatotoxicity.
Authors: Hamada Akinobu , Kai Yuki , Sasaki Jiichiro , Saeki Sho , Kishi Hiroto , Fujii Shinji , Semba Hiroshi , Isobe Takeshi , Hashimoto Yutaka , Kohrogi Hirotsugu , Saito Hideyuki 
Published: March 2020

e13072 Background: Erlotinib is metabolized by cytochrome P450 enzymes to form a para-hydroxyaniline metabolite that is further metabolized to quinone-imine. Erlotinib is detoxified when it conjugates with sulfate or glucuronide. We recently demonstrated that patients who experienced severe erlotinib-induced hepatotoxicity had higher metabolic ratios of glucuronides than those who developed moderate toxicity; this finding indicates that glucuronidation could be saturated and high levels of reactive metabolites might be trigger of glutathione (GSH) depletion. Ophthalmic acid (OA), which is an analog of GSH, may be a useful biomarker for hepatotoxicity because it is a sensitive indicator of GSH depletion in animal model. GSH acts as an enzyme-catalyzed antioxidant when cells and organisms experience electrophilic stress that arises from metabolic processes. Here, we examined the association between plasma concentration of OA and hepatotoxicity in patients who were treated with erlotinib in Japanese patients. Methods: We assessed data from 26 patients with NSCLC who each received a 150 mg dose of erlotinib. Plasma concentrations of OA and erlotinib were measured at before treatment using the liquid chromatography-quadrupole mass spectrometer system. Results: All 26 patients experienced one or more erlotinib-induced adverse events. The most frequent erlotinib-induced adverse events were mild to moderate skin rashes and diarrhea. There seemed to be a relationship between the plasma concentration of erlotinib and the grades of skin rashes and diarrhea. Interestingly, OA was detected only in one patient who developed grade 4 hepatotoxicity, indicating that this patient, who had a higher level of OA (36.9 ng/mL) in plasma. In contrast, the other 25 patients, who did not develop hepatotoxicity, had no detectable OA in plasma. Thus, the plasma concentration of OA was not related to the plasma concentration of erlotinib nor to the grade of skin rash. Conclusions: OA might be useful as a predictive biomarker of hepatotoxicity if measured before starting erlotinib treatment. Larger studies are needed to investigate the association between OA levels and the development of severe hepatotoxicity.
Pharmacokinetic study of clofarabine: Oral bioavailability and the effect of cimetidine on renal clearance.
Authors: Foster Matthew Charles , Kumar Parag , Walko Christine Marie , Ivanova Anastasia , Ewesuedo Reginald , Van Deventer Hendrik , Garcia Reynaldo , Park Steven I. , Shea Thomas C. 
Published: March 2020

e13074 Background: Clofarabine (CLO) is a purine analog with activity in myeloid neoplasms. Its oral dosing has been based on an estimated bioavailability (F) of 49% from uncontrolled trials. Animal models suggest that CLO renal clearance (CL) may be impaired in the presence of inhibitors of organic cation transporter-2 (OCT2), which mediates transport across the renal tubular basolateral membrane. We conducted a pharmacokinetic (PK) study of CLO to determine F, and examine the effect of the OCT2 inhibitor, cimetidine (CIM) on intravenous (IV) CLO. Methods: Patients had: 1) untreated AML ≥ 60 years of age unsuited for standard induction, 2) relapsed or refractory AML, or 3) MDS after failure of ≥ 1 prior regimen. Treatment was: CLO 15 mg/m2 IV day 1, CLO 30 mg/m2 orally (PO) day 3, CLO 15 mg/m2 IV day 5 preceded by two doses of oral CIM, and CLO 30 mg/m2 PO on days 6 and 7. PK studies were obtained after CLO dosing on days 1, 3 and 5. For each dose, CLO plasma concentration was determined, and concentration-time data was analyzed by non-compartmental methods. F was determined for each patient. The geometric means of area under the curve (AUC), 0-∞, and CL for IV CLO administered after CIM doses were compared with AUC and CL for IV CLO administered without CIM. Results: Interim data for the first ten treated patients, with comparisons of PK parameters are shown in the table below. Conclusions: Using patients as their own controls, F of CLO is higher than previously estimated. AUC of CLO is increased and CL is decreased in the presence of CIM, likely owing to inhibition of OCT2-mediated renal tubular secretion. This study is the first human trial to suggest that CLO CL may be impaired in the presence of OCT2 inhibitors, such as cimetidine, trimethoprim, verapamil and nicotine. [Table: see text]
Tolerability of split-dose oprozomib (ONX 0912) in patients with advanced refractory or recurrent solid tumors.
Authors: Papadopoulos Kyriakos P. , Mendelson David S. , Tolcher Anthony W. , Burris Howard A. , Gordon Michael S. , Bomba Darrin , Gillenwater Heidi H. , Infante Jeffrey R. 
Published: March 2020

e13077 Background: Oprozomib (ONX0912), a structural analog of carfilzomib, is an orally bioavailable proteasome inhibitor that irreversibly binds to its target and is being evaluated in hematologic malignancies and solid tumors (ST). In a dose-escalation study of once-daily (qd) ONX0912, the maximum tolerated dose (MTD) was 150 mg/d. The protocol was subsequently amended to investigate the effects of a split-dose schedule. Presented here are the interim results from this patient (pt) group. Methods: This is an ongoing, phase 1 study in pts with advanced refractory or recurrent ST. The primary objective is to evaluate the safety and tolerability of ONX0912 and determine the MTD. ONX0912 is administered for 5 consecutive days in 14-day cycles. For pts under the amended regimen, treatment is initiated at 60 mg BID, with 4–6 h between doses. Daily doses are escalated in 30 mg increments in successive groups of 3 pts. Groups are expanded to include 6 pts in the event of a dose-limiting toxicity (DLT) or if the MTD is reached. All AEs, including serious AEs (SAEs), are defined per protocol and collected from screening to 30 days after the last dose. Results: 13 pts received a split dose of ONX0912 (4 pts: 60 mg BID; 3 pts: 90/60 mg; 6 pts: 90 mg BID). At least 1 dose reduction was required by 1 pt in the 90/60 mg group and 2 pts in the 90 mg BID group. 9 pts reported treatment-related GI AEs (vomiting, n=9; nausea, n=8; diarrhea, n=5). 2 SAEs, arthralgia and mental status change, were reported at 60 mg BID. 2 SAEs resulting in a dose delay were reported at 90/60 mg (Grade 3/4 anemia [ongoing, also required a dose reduction] and reversible fatigue). There was 1 DLT at 90 mg BID (Grade 3 reversible hypophosphatemia), and this cohort was therefore expanded. Treatment-related vomiting led to discontinuation for 1 patient at 60 mg BID. No AEs led to early withdrawal, and no deaths have been reported in the study. Conclusions: With qd administration, the MTD of ONX0912 was established at 150 mg/d. However, the MTD has not been reached on the split-dose regimen at cumulative doses up to 180 mg/d (90 mg BID). GI AEs were the most common treatment-related AEs. Based on these preliminary observations, split-dose ONX0912 may improve tolerability over qd dosing.
WIDEN: A tool for medical imaging management in oncology clinical trials.
Authors: Chauvie Stephane , Biggi Alberto , Stancu Alexandru , Cerello Piergiorgio , Gallamini Andrea 
Published: March 2020

e13093 Background: Recently a novel clinical trial generation based on a therapeutic strategy driven by early treatment response assessment to therapy by functional imaging was conceived and a central review of the images became necessary. We describe hear the application of a new web-based tool for imaging exchange and online review of PET scan (WIDEN) conceived for the prospective multicenter clinical trial HD0607. Methods: In the HD 0607 clinical trial 367 patients affected by advanced-stage Hodgkin Lymphoma (HL), are treated with 2 ABVD courses and a PET scan performed afterwards (PET-2). PET-2 positive patients shift to an aggressive treatment, PET-2 negative patients continue with ABVD. PET-2 along with the baseline scan (PET-0) is uploaded to a dedicated web site thanks to WIDEN and hence distributed to six expert reviewers. The latter report the scans within 72 hours from the upload and determine the choice whether intensify or not the treatment intensity (NCT identifier 00795613). Results: The average (median) time per scan upload and download were 6’39” (1’35”) and 3’26” (1’53”) respectively. The average (median) PET scan size were 133.8 MB (121.5 MB), with a minimum size of 51.2 MB and a maximum size of 469.8 MB. The average (median) time frame between the case files upload by the submitting centre and the case review reporting was 48h 45‘ (40h 31’). 7% of the cases were reviewed among the forth and the fifth days. 3% cases were reviewed after the fifth days. In all cases of a review time spanning over more than three days the delay depended on the presence of a week-end of other holiday time. Concordance rate among reviewers measured with Krippendorff,s alpha was 0.799. Conclusions: WIDEN proved to be an effective tool for medical imaging exchange and review. Data security, simplicity, low cost, feasibility and prompt scan review were demonstrated. Its applicability in any clinical trial in which imaging is decisional for treatment modulation is warranted
A phase I trial to determine the maximum tolerated dose and evaluate the safety and pharmacokinetics (PK) of docetaxel-PNP, polymeric nanoparticle formulation of docetaxel, in subjects with advanced solid malignancies.
Authors: Jung Kyung Hae , Kim Kyu-Pyo , Yoon Dok Hyun , Hong Yong Sang , Choi Chang-Min , Ahn Jin-Hee , Lee Dae Ho , Lee Jae-Lyun , Ryu Min-Hee , Ryoo Baek-Yeol , Chang Heung-Moon , Kim Tae Won , Kim Sung-Bae , Kim Sang-We , Suh Cheolwon , Kang Yoon-Koo , Lee Jungsin , Bae Kyun-Seop , Kim Yong-Man 
Published: March 2020

e13104 Background: The aim of this study was to determine the maximum tolerated dose (MTD) and recommended dose of docetaxel-PNP when administered every 3 weeks in patients with advanced solid malignancies. Methods: Three to six patients received docetaxel at dose levels of 20-75 mg/m2 as 60-min infusions every 3 weeks according to the single dose-escalating 3+3 method. Blood samples at the first dose of docetaxel-PNP were collected for PK analysis. Results: Nineteen pts were treated for a median of two cycles (1-14) in the phase I study. Dose escalation was performed up to 75 mg/m2. The most frequently reported adverse events were grade 4 neutropenia (52.6%, 10/19), grade 1 myalgia (42.1%, 8/19) and grade 1 alopecia (42.1%, 8/19). No acute infusion reactions were noted. Two dose-limiting toxicity was observed at 20 and 60 mg/m2, which were grade 3 hypophosphatemia and death of unknown cause, respectively. Although the MTD was not determined, the recommended dose was determined as 60 mg/m2. This was based on neutropenia and PK parameters which are summarized in the table. PK parameters revealed dose linearity. Partial response was seen in one patient and stable disease in seven patients. Conclusions: Administration of docetaxel-PNP was well tolerated up to 60 mg/m2 every 3 weeks by heavily pretreated patients. Further phase II trials are recommended at this dose level. [Table: see text]
Investigating the utilization of pharmacokinetic-guided fluorouracil in colorectal cancer.
Authors: Patel Jai Narendra , O'Neil Bert H. , McLeod Howard L. , Sherrill Gary Bradley , Olijade Oludamilola , Inzerillo John J. , Atluri Prashanti , Chay Christopher H. , Walko Christine Marie 
Published: March 2020

e13109 Background: Fluorouracil (FU) has remained the cornerstone of colorectal cancer (CRC) therapy for > 40 years; however, recent evidence suggests inter-individual pharmacokinetic (PK) variability in response. Methods: A total of 58 CRC patients from 6 academic and community sites received mFOLFOX6 (FU 2400 mg/m2 over 46 hours every 2 weeks) +/- bevacizumab. FU doses for cycles 2-4 were adjusted based on an algorithm to target an AUC of 20-25 mg*h/L. Peripheral blood was obtained 2-46 hours post beginning of infusion (BOI) and AUCs were determined using an immune-based assay (OnDose). The primary objective of this study is to describe the feasibility of PK-guided FU in clinical practice using descriptive statistics with a secondary objective of toxicity assessment. Results: Mean AUC post cycle 1 in evaluable patients (n=39) was 19.8 +/- 6.3 mg*h/L (range 7-38) with 31% within, 51% under, and 18% over the AUC target. Based on cycle 1 results, the mean dose estimated to achieve AUC 20-25 mg*h/L would be 2,505 +/- 304 mg/m2 (range 2,040-3,600). For cycle 1, the mean AUC at 2 and 18-24 hours post BOI was 17.5 +/- 6.9 and 21.6 +/- 6.3, respectively. Of 58 patients, 19 were not evaluable due to logistical issues such as sampling errors, dosage deviation from protocol, no stabilizing agent added to sample, or the patient was unable to return to clinic for sampling. Three hospitalizations due to serious adverse events occurred, with 2 at AUCs > 30. See the table for toxicities. Conclusions: Significant heterogeneity is noted in FU AUC with BSA-based dosing, with the majority of patients below the protocol-specified AUC threshold. Although FU should be at steady-state 2 hours post BOI until the end of infusion, a difference in AUC was seen between samples taken at 2 and 18-24 hours. With little study withdrawal observed after initial patient enrollment, appropriate logistical training can allow for individualization of FU in the front-line, community setting for the treatment of CRC; however, larger clinical trials are needed to define the clinical utility of PK-guided FU. [Table: see text]