bluuebunny/crossref_metadata_2025_split huggingface dataset:
A phase I study of NGR-TNF, a novel vascular targeting agent, in patients with refractory solid tumors (EORTC 16041)
Authors: Heerschap A. , Fiedler W. , Marreaud S. , van Laarhoven H. , Govaerts A. , Peters M. , Toma S. , Bordignon C. , Punt K. , Van Herpen C. 
Published: March 2020

14074 Background: NGR-TNF is a novel agent exploiting a tumour homing peptide (cNGRCG) that selectively targets CD13 that is expressed on the neovasculature of solid tumors. Preclinical data show that its antitumour activity is achieved by a change of vascular permeability (at low doses) and damage of tumour-associated blood vessels (at high doses). This phase I study is being conducted to assess its safety, PK, PD, MTD, and optimal biological dose in patients (pts) with advanced solid tumours. Methods: NGR-TNF was administered once every 3 weeks by a 20 min IV infusion to cohorts of 3–6 pts. The starting dose was 0.2 μg/m2. Dose escalation was performed with a doubling of the dose until grade 2 toxicity was observed; thereafter a modified Fibonacci schedule was used. PK and PD analysis in blood was performed during the first 4 cycles. DCE-MRI was performed in cycle 1 at baseline and 2 hours after start of the infusion to document modification of the tumour vascularity. Anti-tumour activity was assessed by CT scan every 2 cycles. Results: 45 pts were treated and 133 cycles of treatment completed up to now. 12 DLs have been visited (0.2 to 14.36 μg/m2). One DLT (bronchospasm G 3) was observed at DL4 (1.3 μg/m2) and the DL was extended to 7 pts. As no other DLT was observed, dose escalation was continued. Since then no additional pt experienced dose-limiting toxicity. As 3/18 first pts experienced chills G 2 during injection time, the study was amended and infusion time increased to 1 hour. Since then 1/14 next pts had G 2 chills. Overall most frequently related adverse events reported in the first 34 pts: chills 76%, fever 44%, nausea 20%, constipation 12%, diarrhea 9%, anorexia and hypotension 6%. PK/PD analysis for the plasma levels of TNF-RI and TNF-RII showed a better profile for the 60 min compared with the 20 min infusion. At DL = 1.3 μg/m2 most pts showed a decrease in kep and the number of pixels with a low fraction of kep and Ktrans significantly increased (p<0.05), as seen with other anti- vascular agents. Stable disease was observed in 39% of pts, with a median duration of 11 wks (range 5–36). No responses were observed. Conclusions: NGR-hTNF is well tolerated and some biological activity was observed by DCE-MRI. Study enrollment is ongoing. [Table: see text]
First-in-human phase I trial of a cyclodextrin-containing polymer-camptothecin nanoparticle in patients with solid tumors
Authors: Yen Y. , Synold T. , Schluep T. , Hwang J. , Oliver J. , Davis M. E. 
Published: March 2020

14078 Background: IT-101 is a de novo designed experimental therapeutic comprised of linear, cyclodextrin(CD)-containing polymer conjugates of camptothecin(CPT) that assemble into ca. 40 nm diameter nanoparticles via polymer-polymer interactions that involve inclusion complex formation between the CPT and the CD. Particle size, near neutral surface charge and CPT release rate were specifically designed into IT-101. Published pre-clinical animal studies show extended circulation times (t1/2 of ca. 20 h in rodents), tumor accumulation, slow release of the CPT and anti-tumor efficacy that directly correlate to the properties of the nanoparticle. Release of CPT can disassemble the nanoparticle into individual polymer chains that have size ca. 10 nm that are capable of renal clearance (t1/2 of several minutes in rodents). Methods: Patients with relapsed or refractory cancer were evaluated every two cycles of therapy (90 minute IV infusions of IT- 101 in D5W on days 1, 8 and 15 of a 28 day cycle). Three dose levels of 6, 12 and 18 mg CPT eq./m2 have been tested. Results: At the time of this interim analysis, eight patients have been enrolled and five evaluated. In general, IT-101 is well tolerated and pancytopenia is the DLT. The expected MTD is 12 mg/ m2.Three out of five patients demonstrated stable disease on CT scan evaluation. One pancreatic cancer patient remains stable for 6 months. PK data are available from the first 5 patients. Total and free CPT display biphasic elimination from plasma with mean terminal elimination half lives of 38±3.7 and 61±43 hours, respectively. The mean Vd and CLsys of total CPT are 6.1±1.4 L and 0.1±0.03 L/h and are unrelated to dose over the range tested, with a mean total-to-free AUC ratio of 10.7±3.7. Conclusions: These first in human PK data for IT-101 confirm that 40 nm particles with near neutral surface charge provide favorable PK properties. The stable disease rate, although not yet conclusive, is consistent with promising efficacy. The preliminary results of this phase I study warrant continued enrollment that is ongoing. No significant financial relationships to disclose.
Oblimersen can be administered by subcutaneous (SC) and brief intravenous (IV) infusion: Clinical pharmacokinetics and pharmacodynamics (PK/PD) in patients with advanced cancer
Authors: Lin C. , Papadopoulos K. , Patnaik A. , Sankhala K. , Takimoto C. H. , Rodon J. , Julian T. , Brown B. D. , Tolcher A. W. 
Published: March 2020

14083 Background: Oblimersen (OBL) is a phosphorothioate oligodeoxynucleotide that decreases Bcl-2 protein levels. OBL has been administered by continuous intravenous infusion (CIVI) in most clinical studies. However, recent preclinical data suggest that equivalent or superior antitumor efficacy can be achieved with intermittent administration. We conducted a dose-ranging PK/PD study of OBL given by bolus SC injection and brief IV infusion to evaluate the feasibility of intermittent dosing. Methods: In this within-subject dose-escalation study, OBL was administered subcutaneously (SC) at doses of 75, 150 and 225 mg. In part II of the study, OBL was administered by 2-hr IV infusion beginning at 150 mg on day 1, by single-dose SC injection on day 8, and 2-hr IV daily x 5 consecutive days. Pharmacokinetics were assessed by non-compartmental analysis. Pharmacodynamic measurements of Bcl-2 levels in peripheral blood mononuclear (PBM) cells were made using Western blot analysis. Results: OBL absorption after SC administration was rapid with a Tmax of ∼2 hours. Mean Cmax values were 0.76, 1.70 and 3.10 μg/ml for the 75, 150 and 225 mg SC doses, respectively. Mean AUC0- inf values were 7.78, 15.36 and 25.57 hr*μg/mL. Plots of dose-normalized Cmax and AUC vs. dose showed slopes close to zero, indicating approximate dose proportionality. AUC0–24 exposure with the 225 mg SC dose was similar to previously established 24-hr steady-state AUCs after 3 mg/kg CIVI. SC injection was associated with an inflammatory erythematous grade 1 rash at the injection site that resolved within 7 days. The 150 mg 2-hr IV infusion x 1 or daily x 5 has been well-tolerated. Conclusions: OBL exposure from a single SC injection is similar to a 24-hr 3 mg/kg CIVI, and the 2-hr IV infusion is currently being evaluated. Both schedules appear to be well- tolerated, may reduce requirements for CIVI, and could be incorporated into intermittent dosing regimens. No significant financial relationships to disclose.
Phase I study of CYT997, a novel cytotoxic and vascular disrupting agent, given as a 24-hour intravenous infusion to patients with advanced solid tumours
Authors: Lickliter J. , Smith G. , Burge M. , Coulthard A. , Wyld D. , Wilks A. , Vasey P. 
Published: March 2020

14115 Background: CYT997 is a novel tubulin-binding small molecule which inhibits microtubule assembly and also demonstrates potent vascular-disrupting activity in preclinical tumour models. Methods: CYT997 was administered by continuous infusion over 24 hours every 3 weeks to patients with advanced cancer. Dose escalation proceeded by a standard phase I design (3 patients per dose level) for the first 18 patients; subsequently, an accelerated titration design (1 patient per dose level) was utilized. Intrapatient dose escalation was permitted. Pharmacokinetic (PK) analyses were performed in the first cycle. Tumour response was determined every second cycle using RECIST criteria. Pharmacodynamic effects on the tumour vasculature were assessed with dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI). Results: 22 patients (M/F: 11/11; median age 57.5, range 28–75) were enrolled with tumour types including melanoma (4), renal cell (4), colorectal (2), non-small cell lung (2) and adenoid cystic (2) carcinomas, mesothelioma (2) and others (6). A total of 66 cycles of CYT997 were administered (median 2/patient, range 1–6) over 10 dose levels (7, 14, 23, 35, 49, 65, 86, 114, 152 and 202 mg/m2). No dose-limiting toxicity was observed. Because of grade-2 injection site reactions in 2 patients (one each at dose levels 3 and 4), all subsequent patients received CYT997 via a central venous access device. Other toxicities included grade-2 renal toxicity at dose- level 8 in one patient with abnormal baseline renal function and grade-1 QTc prolongation in one patient at dose-level 10. No myelosuppression, gastrointestinal toxicity or clinically-significant cardiac toxicity were observed. PK data revealed dose-related increases in Cmax and AUC values. Six patients had stable disease after 4 cycles of CYT997. Conclusions: CYT997 was well tolerated at the doses studied and accrual to the 269 mg/m2 dose level will now proceed. No significant financial relationships to disclose.
A phase 1 study of the selective cyclin dependent kinase inhibitor P276–00 in patients with advanced refractory neoplasms
Authors: Hirte H. W. , Raghunadharao D. , Baetz T. , Hotte S. , Rajappa S. , Iacobucci A. , Sharma S. , Parikh H. , Kulkarni S. , Patil S. , Gaston S. 
Published: March 2020

14117 Background: In human cancers, genetic and epigenetic events result in over-expression of cyclins or absence or diminished levels of Cdk inhibitors, providing tumor cells with selective growth advantage. This has prompted the development of pharmacological Cdk inhibitors that could potentially produce anti-tumor effect. P276–00 is a selective Cdk4-D1 and Cdk1-B inhibitor. This study was designed to determine the maximum tolerated dose (MTD), toxicity profile, pharmacokinetics, and antitumour activity of P276–00 given intravenously to patients with advanced refractory solid tumours. Methods: P276–00 was administered in escalating doses to cohorts of eligible patients (pts), starting with a dose of 9 mg/m2 as a 30 minute iv infusion day 1 to 5, and day 8 to 12, q 3 weekly. To date 22 pts have been entered on the study (cohort 1 - 4 pts at 9 mg/m2, cohort 2 - 4 pts at 12.6 mg/m2, cohort 3 - 6 pts at 17.6 mg/m2, cohort 4 - 8 pts at 24.6 mg/m2) with PS 0–2, and mean age of 56 years. Pharmacokinetic profiles were obtained on cycle 1 days 1 and 5. Skin biopsies were obtained immediately prior to starting study treatment and on day 21 of cycle 2 and will be analyzed for Ki67, cleaved caspase 3, phospho-Rb, cyclin D1 and cdk4, and microarray. Results: To date dose limiting toxicity has occurred in one pt. Grade 3 fatigue occurred in 1 pt at 17.6 mg/m2. The most common drug-related adverse events, which were all grade 1 or 2, were fatigue, nausea, hypotension, sweating, and dry mouth. No Grade 3 biochemical toxicities have been reported so far. There have been no responses noted to date. 4 pts have stable disease after 2 cycles. Pharmacokinetic results: The Cmax, t1/2, and AUC0–8 on day 1 were as follows: 9 mg/m2- 315 ng/mL, 6.6 hr, 883 ng.h/mL; 12.6 mg/m2- 402 ng/mL, 5.5 hr, 848 ng.h/mL; 17.6 mg/m2- 589 ng/mL, 5.3 hr, 1289 ng.h/mL; 24.6 mg/m2- 621 ng/mL, 5.6 hr, 1286 ng.h/mL. Conclusions: P276–00 is well tolerated, but grade 3 fatigue has been noted in 1 pt at 17.6 mg/m2 dose level. We have observed confirmed stable disease in one patient. PK results indicate that at 9 mg/m2,12.6 mg/m2, 17.6 mg/m2 and 24.6 mg/m2 we are able to cross the cdk4 enzyme IC50 approximately 10, 13, 19 and 20 times and cross the anti-proliferative IC50 1.1, 1.4, 2.1 and 2.2 times respectively. Accrual continues at the 34.4 mg/m2 dose level. No significant financial relationships to disclose.
Reversible tumor metastases growth acceleration following bevacizumab interruption and surgical resection of metastases
Authors: Boisserie T. , Cacheux W. , Vignaux O. , Dousset B. , Soubrane O. , Chaussade S. , Goldwasser F. 
Published: March 2020

14119 Background: The addition of bevacizumab (BV), an anti-VEGF monoclonal antibody with antiangiogenic activity, to cytotoxic chemotherapy (CH) improves survival in metastatic colorectal cancer patients (pts). Reversal of VEGF inhibition is associated with rapid vascular regrowth in tumors in vivo (M.R. Mancuso et al, J Clin Invest; 116(10): 2610–2621, 2006). In the clinical setting, the consequences of BV interruption are poorly documented, especially in interactions with the surgical resection of liver metastases. Methods: We describe the kinetics of tumor growth prior to, during, and after interruption of BV and under BV reintroduction, in consecutive colorectal cancer pts experiencing objective response under CH+BV, followed by surgical resection of metastases. We measured either clinically, of using CT-scan, the diameter of target lesions according to RECIST criteria, and the doubling time. Results: 7 pts (3 F, 4M), with median age of 54 years (41–70), were treated with 5-FU based CH (+oxaliplatin: 5; + irinotecan: 1 pt) and BV for metastatic colo- (6 pts) rectal (1 pt) cancer received a median number of 6 (4–18) cycles. Median time between BV interruption and surgery: 8 weeks (3–12). Under BV, all pts experienced objective response, with a median tumor reduction of 13%/month (extr: 6–15%). After BV interruption, under CH alone, 2/7 pts experienced disease progression, with a tumor growth of the residual disease of +7% and +200%/month, respectively. In pts who underwent surgery, during the off therapy period, tumor growth occurred in all 7 pts with a kinetics of +17 to +400%/month. Tumor growth doubling time after BV interruption ranged between 2 and 5 weeks. Reintroduction of BV re-induced a tumor response in 5/7 pts with a median time to response of 8 weeks (6–12) and a reduction of 10%/month. Conclusions: We show reproducible evidence of tumor growth acceleration following BV interruption. Surgery might transiently modify the balance between angiogenic and anti-angiogenic factors. We suggest to reduce the duration of BV interruption and to restart BV as soon as possible after surgery. These observations justify a large prospective analysis of the variations of tumor growth in this setting. No significant financial relationships to disclose.
Silibinin’s effect on total EGFR, Erb-b2, and Erb-b3 expression in human colon cancer
Authors: Hogan F. , Krishnegowda N. K. , Kahlenberg M. S. 
Published: March 2020

14124 Purpose: Flavonoid, silibinin, has been shown to have strong chemotherapeutic activity in prostate, breast, bladder, skin, ovarian, and colon cancer. It has no documented LD50 and has been proven safe in multiple animal models and human trials. Cell cycle arrest and inhibition of protein levels of various cyclins are commonly reported in silibinin’s mechanism of action. We investigated silibinin’s activity on upstream cell-signaling targets, EGFR, Erb-b2, Erb-b3, Akt, Erk1/2, and mTOR, using three human colon cancer cells lines: Fet, Geo, HCT 116. Methods: The MTT cell-viability assay and FACS analysis were performed after silibinin treatment to substantiate its effect on proliferation and cell-cycle. Western blots for EGFR, Erb-b2, Erb-b3, Erk1/2, Akt, and mTOR were completed and quantified with densitometry. Standardization of protein loading was confirmed with cytoskeletal and house-keeping proteins, B-actin and GAPDH. Means were contrasted using analysis of variance with Dunnet’s correction for multiple testing. All statistical testing was two-sided with a significance level of 5%. Results: The MTT assay revealed a dose-dependent inhibitory effect. Treatment of FET and GEO at 75 micrograms/ml resulted in 50% inhibition of cell-viability (IC-50) at 72 hrs. An IC50 dose of 40 ug/ml was established for HCT116. FACS analysis demonstrated statistically significant cell-cycle arrest in all cell lines. G2-M phase arrests in Fet and Geo cell lines (p<0.001) and a G1 arrest in HCT116 (p=0.005) were noted. Western blots showed decreased protein level expressions of total and phospho-EGFR, Erb-b2, Erb-b3, Akt, Erk1/2, and mTOR. Conclusions: Inhibition of protein expression levels of the Erb-b family of receptor tyrosine kinases plays a role in the mechanism of silibinin’s action. Strong inhibition of protein levels of total EGFR, Erb-b2, and Erb-b3 was noted as well as downstream decreases in total Erk1/2, Akt, and mTOR. Given silibinin’s inhibition of cancer proliferation and its safety profile, it is a promising compound requiring further mechanistic study, and applications in cancer therapy should be pursued given its effects on the Erb-b class of receptor tyrosine kinases and intermediary proteins, Erk1/2, Akt, and mTOR. No significant financial relationships to disclose.
Anti-lactadherin antibodies in anti-angiogenic cancer therapy of breast cancer stem cells
Authors: Epenetos A. A. , Bower G. , Deonarain M. , Bonney L. 
Published: March 2020

14138 Background: Angiolix (Hu-Mc3) is a humanized monoclonal antibody that recognizes a migrating adhesion molecule called Lactadherin. This novel antibody has a high affinity for its antigen and recognizes an epitope on Lactadherin which interacts with the the ’RGD’- motif found on integrin receptors on newly formed endothelial cells. Lactadherin binding leads to signalling via a VEGF-independent integrin receptor signalling cascade leading to vascular endothelial cell profileration. Lactadherin binding may also increase the potency of VEGF-VEGF receptor signalling. Methods: We studied the expression of Lactadherin on breast cancer cell lines, the biodistribution of Angiolix in human breast cancer xeografts and its ability to inhibit tumor growth in vivo. Results: Our data show that tumor cells express lactadherin in vivo and that Angiolix could achieve more than 75% growth inhibition of human breast cancer growing as xenografts . Conclusions: In view of the recent finding that cancer stem cells can over-express the pro-angiogenic VEGF and make a major contribution to tumor vasculature proliferation leads to the possibility that Angiolix may be able to act to specifically target breast cancer stem cell and cause tumor regression by blocking the growth of tumor vasculature by its ability to neutralise Lactadherin-integrin receptor binding. [Table: see text]
Can antisense oligonucleotides targeted K-ras gene downregulate the expression of MMP-2 and MMP-9 in orthotopically implanted pancreatic cancer in Syrian golden hamsters
Authors: Morioka C. Y. , Costa F. P. , Saito S. , Lima E. M. , Watanabe A. , Huang C. C. 
Published: March 2020

14147 Background: Matrix metalloproteinases (MMP), especially MMP-2 and MMP-9, are thought to play major roles in pancreatic cancer growth and metastasis.Ras activates a multitude of downstream activities with roles in cellular processing, including invasion and metastasis.Therefore, antisense oligonucleotides (ASO) targeting K-ras gene may be a therapeutic approach. Aim: To elucidate the effectiveness of this gene therapy in growth, invasiveness,and expression of MMPs,in hamster experimental pancreatic cancer model. Materials and Methods: HaP-T1,a cell line derived from BHP-induced pancreatic cancer was used.Transfection with ASO were performed.MTT and MTT agarose assays were performed.MMP-2 and MMP-9 production by HaP-T1 was determined by gelatin zymography.For in vivo experiments,subcutaneously resected tumors were implanted orthotopically in Syrian golden hamsters,which were divided in 3 groups:Positive control (PC),Sense treated hamsters (STH), and Antisense treated hamsters (ATH).Follow up was done.Animals of each group were sacrificed at Days 10,17,24,31,and 38,to study local response and metastatic sites.Survival time was studied. Specimens were studied histopathologically.Orthotopic pancreatic tumor MMP production was measured by gelatin zymography. Results: ASO inhibited the tumoral growth.They downregulated active forms of MMP-2 and MMP-9 in a dose dependent manner in vitro.PC,STH,and ATH survived in average 72.7, 74,3, and 82,7 days,respectively.Spontaneous lymph node metastases were found from 31 days in ATH group,while PC and STH groups showed metastases and direct invasion to adjacent organs from 17 days.After death,metastatic sites were similar in the 3 groups.ASO downregulated the activation of MMP-9, more than MMP-2 in vivo. Conclusions: ASO targeted K-ras gene suppressed tumor growth in vitro and in vivo.ASO also downregulated the activation of MMP-2 and MMP-9 in vitro.However, it downregulated more MMP-9 than MMP-2 in vivo.Nevertheless, it can be a good choice in management of pancreatic cancer because MMP play an important role in the process of metastasis. No significant financial relationships to disclose.
Single institutional experience with rituximab in the treatment of B cell lymphoproliferative malignancies and autoimmune disorders
Authors: Jajeh A. , Catchatourian R. , Samuel J. , Hussein L. , Yim B. , Jacob-Sharma J. , Menini P. 
Published: March 2020

14150 Background: This is a retrospective analysis of usage of rituximab( Rituxan) a monoclonal antibodies against CD20 expressing B lymphocytes.The duration of period studied is from December first,2004 to July first,2006.This involved one single institution, John Stroger hospital of Cook County,chicago. Methods: A total of two hundred and thirty 230 treatment courses recorded.This involved a total of 208 patients.Some patients treated with more than one course in combination with different chemotheraputic agents. Results: . A total of 208 patients received Rituxan. Median number of doses is 8 (range 1–18). This include 92 patients with Diffuse large B-cell NHL, six patients with Burkitt’s lymphoma, thirty six patients with low grade NHL, three patients with mantle cell lymphoma, three patients with orbital lymphoma, three patient with AIDS related NHL, twenty seven patients with chronic lymphocytic leukemia CLL, ten patients with MALT/Gastric lymphoma, ten patients with ITP and 7 patient with warm autoimmune hemolysis, 7 patients given Rituxan as part of Rheumatoid Arthritis treatment. The complete response rate CR, near CR, partial response improved with adding Rituxan to 85% in Diffuse large grade Bcell lymphoma, one third high IPI score. Only 15% were refractory or relapsed after response. In low grade Bcell NHL 1/3 of patients received multiple prior treatments and the response rate were improved and disease progression was delayed. Most patients are of younger mean age 55 range (19–80).One third of patients recieved maintenace rituxan .Transfusion reaction occurred in less than 10%, severe leucopenia 3%, GI perforation in one patient, focal leukoencephalopathy PML in one with CNS involvement, tumor lysis syndrome occured in three patients, severe mucocutaneous reaction occured in one patient.One patient with RA and warm immune hemolysis died with sever pancytopenia after two months from recieving four doses. . Conclusions: This is a single institution experience where 60 percents are african american. This also show that Rituxan usage has became a standard therapy in Bcell lymphoproliferative malignancies.The improvement in response rate and progression free survival match other published phase III multicentered studies. No significant financial relationships to disclose.