bluuebunny/crossref_metadata_2025_split huggingface dataset:
Blood pressure (BP) as a biomarker for sorafenib (S), an inhibitor of the vascular endothelial growth factor (VEGF) signaling pathway
Authors: Maitland M. L. , Moshier K. , Imperial J. , Kasza K. E. , Karrison T. , Elliott W. , Undevia S. D. , Stadler W. , Desai A. A. , Ratain M. J. 
Published: March 2020

2035 Background: Hypertension is a commonly reported toxicity of agents that inhibit the VEGF signaling pathway (VSP). This new class of cancer therapeutics has broad activity, but optimal dosing methods and integration into established treatment regimens could be enhanced by identification of reliable biomarkers. S, a new treatment for advanced renal cell carcinoma, is an orally available inhibitor of multiple VSP kinases including Raf-1 and VEGFR2. To characterize the chronicity and interindividual variability of BP responses to VSP inhibition we collected serial, standardized measures of BP and concurrent steady-state plasma concentrations ([plasma]) of S, from 30 patients (pts). Methods: Pts with advanced solid tumors, ECOG performance status < 2, and screening BP ≤ 140/90 mmHg on no more than one antihypertensive agent took 400mg S twice daily. Prior to therapy and at 3 time points after steady state [plasma] of drug was achieved, pts underwent 24-hour ambulatory BP monitoring with the SunTech Oscar PowerPack 2 (SunTech Medical, Morrisville, North Carolina). Readings were collected every 15 minutes during daytime hours and every 45 minutes overnight. Results: Unweigthed mean and standard deviations (sd) of systolic (SBP) and diastolic (DBP) 24-hr BP measurements were calculated for each pt. for the sessions pre-therapy and when steady state [plasma] S was reached (between days 6–10 after starting treatment). The differences in mean BPs between the two sessions were compared with (and p values reported for) paired t-tests. Regression analysis of [plasma] of S with either DBP or SBP, or change in DBP or SBP, with main effect and interaction terms for albumin, age, and sex revealed no significant correlation between S [plasma] and BP response. Conclusions: BP elevation is a biomarker for VSP inhibition. The known variability (coefficient of variation = 70%) in total S steady state plasma concentrations did not account for the observed variability in BP response. [Table: see text] [Table: see text]
Pharmacokinetic (pk) and safety study of irinotecan (Ir) and capecitabine (Cp) administered on a weekly schedule
Authors: Gollamudi R. , Baker S. D. , Desai K. K. , Chaudhary I. , Kaubisch A. , Camacho F. J. , Einstein M. , Goldberg G. , Goel S. , Mani S. 
Published: March 2020

2061 Background: In vitro studies show synergy between Cp and Ir. Since both drugs are metabolized by carboxyl esterases (CE), the potential for competitive inhibition is possible. We conducted a study to identify a safe dose and potential drug-drug interactions of this combination. Methods: This was an open-label phase I dose escalation trial. Ir was given as a 30 min infusion on days 1 and 8, and Cp on days 1–14 of a 21 day cycle. Plasma for pk analyses was drawn on days 1 and 8, at 0, 15, 30, 45, 60, 90, 120, 240, 360 min, and 24 hr, for total CPT-11, SN-38, SN-38-glucuronide (G), and APC. Results: 47 patients (pt) - median age 60 (32–83) years; performance status 0–1 (96%); diagnoses- ovarian (10), breast (5), cervical (5), colorectal (10) and others (17) received 202 (median 4, range 1–18) cycles in 6 dose cohorts - Ir (mg/m2)/Cp (mg/m2/day in 2 divided doses) 75/1500, 85/1500, 85/1750, 100/1750, 100/2000, 115/2000. At the highest dose tested (115/2000), 1 of 3 pt developed grade (G) 4 neutropenia with fatal gram-negative sepsis. At dose level 5 (100/2000), 2 of 21 patients developed cycle 1 DLT - G 3 diarrhea/vomiting and G 3 diarrhea. Across all doses and patients, the G 3–4 toxicities observed were diarrhea (12 pt), vomiting (2 pt), fatigue (5 pt), hand-foot syndrome (1 pt), neutropenia (6 pt), anemia (4 pt), thrombocytopenia (2 pt) and elevation of AST/ALT (1 pt). Anti-tumor responses include partial response in 8 of 35 evaluable (23%) pts (3 breast, 4 ovarian, 1 cervical), a minimal response (1 breast), and a 90% decline in PSA (1 pt). Detailed pk analyses show that AUC(0-∞) of Ir, SN-38G, and APC were similar on days 1 and 8. However, SN-38 Tmax was longer on Day 8 (0.87 hr vs. 1.22 hr, p = 0.012). While SN-38 AUC (0-∞) was higher on day 1 by 45%, this was not statistically significant (p = 0.167). Conclusions: Cp results in a delayed conversion of Ir to SN-38, suggesting competitive inhibition of CE at a molecular level without clinical significance. This could portend a drug-drug interaction when Ir is combined with substrates of CE, and warrants further study. The combination of Ir and Cp is safe and well tolerated at 100/2000, and warrants further evaluation in breast, cervical, ovarian and other malignancies. [Table: see text]
Results of phase I clinical trials of Coramsine in patients with advanced solid tumors
Authors: Millward M. , Powell A. , Daly P. , Tyson S. , Ferguson R. , Carter S. 
Published: March 2020

2070 Background: Coramsine (C) is a 1:1 mixture of solasonine and solamargine, plant glycoalkaloids found in the species Solanum Linneanum, with single agent and synergistic combination in vitro and in vivo preclinical efficacy in various tumor models through interaction with rhamnose-containing cell membrane glycoproteins and subsequent internalization. Methods: C initially as a 2-hr IV infusion daily × 5 every 2 weeks to define the MTD, recommended Phase II dose, toxicity and pharmacokinetics. Based on preclinical toxicology the infusion duration was increased to 4 hours and 24 hours (120 hr continuous infusion). Doses studied range from 0.75 mg/kg/day to 3.0 mg/kg/day. Results: 27 pts were treated. DLT occurred in 2/2 pts at 1.5 mg/kg/day (2 hr) and 2/2 pts each at 3.0 mg/kg/day (4 hr and 24 hr). Preceding dose levels 1.0 mg/kg (2 hr) and 1.5 mg/kg (4 hr) produced DLT in 2/6 pts each with no grade IV. Over 24 hr, 2.25 mg/kg/day produced DLT in 4/6 patients. Limiting toxicity at all schedules was grade III/IV transaminitis with grade I-III increases of bilirubin and grade I-II creatinine. Hepatotoxicity was maximal at days 3–5, resolved over 10–21 days, was clinically asymptomatic apart from grade I-II fatigue, and was not cumulative. No myelosuppression or other serious drug-related toxicity was recorded. Partial responses were documented in 2 pts (renal, NSCLC) and minor response in 1 pt with unknown primary. Responses were seen using both 2 hr and 4 hr infusions. Pharmacokinetic parameters for solasonine and solamargine are linear across the narrow range of doses studied with elimination T1/2 of 5.57 ± 1.27 hr (solasonine), 8.40 ± 2.00 hr (solamargine) and Cl of 5.6 ± 1.6 L/hr (solasonine), 3.0 ± 0.7 L/hr (solamargine). Peak levels of both exceed active in vitro levels (>2,000 ng/ml). Conclusions: Coramsine produces dose-limiting hepatotoxicity at doses above 1.0 mg/kg/day over 2 hours or 1.5 mg/kg/day over 4 hours. 2.25 mg/kg/day over 24 hours exceeds the MTD. Activity has been seen against resistant solid tumors. Phase II studies in renal cancer and melanoma will be performed using 1.5 mg/kg/day over 4 hours. [Table: see text]
Predictive computer simulations of tumor drug response demonstrate that 3-D hypoxic gradients significantly increase drug resistance
Authors: Cristini V. , Frieboes H. , Fruehauf J. 
Published: March 2020

2071 Background: We created a three-dimensional physiologically based computer (in-silico) model of cancer based on a description of biological events at the cellular scale with input variables determined from patient specific information, such as in-vitro drug response experiments and in-vivo tumor imaging, with the long term goal of individualized treatment selection. The central hypothesis is that such a model that incorporates basic tumor growth kinetics information is capable of representing and predicting tumor response to chemotherapy. Methods: We measured in-vitro tumor growth and drug response for Doxorubicin sensitive and resistant MCF-7 breast cancer cells through trypan blue exclusion counts, tridiated thymidine incorporation, and the XTT assay. We used these results of parameter-based statistics to define input variables to our in-silico model of cancer, and ran computer simulations to measure the drug response predicted by the model. Results: The computer model could accurately predict the in-vitro response of drug sensitive and resistant MCF-7 breast cancer cells. The model also predicted that gradients of oxygen and nutrient in a tumor microenvironment, whether naturally occurring or induced by treatment, and which in previous work we found could increase the invasive capability of tumor cells and destabilize tumor morphology, could also contribute to acquired drug resistance by increasing the population of quiescent cells. Conclusions: We demonstrated that a rigorously, experimentally calibrated computer model of cancer is accurately predictive of in-vitro tumor response to chemotherapeutic drugs, and established that this model offers a means to quantitatively study tumor drug response. We did this through a grounds-up physical representation of tumor biology, not by fitting to experimental data. This validation begins the path to computational modeling and more efficient prediction of in-vivo tumor response to chemotherapy. No significant financial relationships to disclose.
Stromal cells extracted from ovarian cancer express functional multi drugs resistance proteins: ATP bindig casset and Major vault protein
Authors: Rafii A. , Mirshahi P. , Simon A. , Faussat A. , Ducros E. , Marie J. , Pujade-Lauraone E. , Soria J. , Mirshahi M. 
Published: March 2020

2072 Background: Stromal cells play a central role for the growth of tumor cells. The functional contribution of these cells in cancer therapy is poorly understood. Here we studied the presenceofthe proteins ABC (ATP binding Cassette) and MVP (Major vault protein) implicated in the multi drugs resistance (MDR) phenomena in stromal cells isolated from ascitis of patients with ovarian carcinoma. Methods: Stromal cells were extracted from ascitis of patients with ovarian carcinoma. The expression of MDR proteins as p-gp (Permeability-glycoprotein), BCRP (breast cancer resistance protein) and MRPs (multidrug related proteins) as well as LRP (lung resistance protein that is a MVP) was studied by two different technique (immunocytochemistry and flow cytometry) using specific antibodies against these proteins. The functionality of the pumps or efflux, was studied by incorporation of fluorescent probes, Rhodamine 123 and JC1, substrate for p-gp, calcéine-AM substrate for p-gp and MRPs and at last Mitoxantrone substratum of BCRP, in the presence of specific inhibitors: as the cyclosporine HAS, the GG918 and the MK571 for the pumps Pgp, BCRP and MRPs respectively. Then the expression of the genes was assessed by RT-PCR. Results: 1) The expression of the proteins ABC is confirmed by immunocytochemistry and by flow cytometry. The Pgp and LRP proteins were strongly expressed and they are functional, the MRP-1, 2, 3 and BCRP proteins are weakly expressed and the MRP-5 protein is not detected. 2) The RNAm corresponding to all of these proteins is found by RT-PCR in the stromal cells. Conclusions: All of these results suggest that the MDR proteins are present on the cells surface of the tumour cell microenvironnement. The functionality of these proteins allows supposing their implication in the phenomena of multi drugs resistance to chemotherapy. The interaction between cancer cells and stromal cells should be targeted during specific chemotherapy. No significant financial relationships to disclose.
Phase I dose-escalation study of novel oral multi-target tumor growth inhibitor (MTGI) ZK 304709 administered daily for 7 days of a 21-day cycle to patients with advanced solid tumors
Authors: Graham J. , Wagner K. , Plummer R. , Wiedenmann B. , Cassidy J. , Kowal K. , McCoy C. , Calvert H. 
Published: March 2020

2073 Background: ZK304709 is a novel MTGI that selectively inhibits activity of Cyclin Dependent Kinases (CDKs) 1, 2, 4, 7, 9, and the tyrosine kinase activity of VEGF-R 1, 2, 3 and PDGF-βR. Methods: Adult patients (pts) with a good performance status (WHO PS ≤2) and a histologically or cytologically confirmed relapsed/refractory solid tumor were eligible. ZK304709 is administered, as a monotherapy, orally on days 1–7 of a 21-day cycle to fasting patients at a starting dose of 15 mg qd. Dose escalation has ranged from 33% - 100% of prior dose, depending on occurrence of drug-related toxicity ≥ grade (gr) 2 (CTC v2.0). Between 3 and 7 patients are to be enrolled per dose level, depending on DLTs that are observed. The primary objective is determination of the maximum tolerated dose (MTD) and dose-limiting toxicities (DLT) of ZK304709. Secondary objectives include tolerability, pharmacokinetic (PK) profile, and preliminary efficacy. Results: Interim results are available for 22 pts (15 M/7 F, median age 60.5 yrs; range 37–71) treated with ZK304709 at 6 dose levels (15 - 180 mg qd). Patients completed a median of 2 cycles (range 0–8). Common AEs were nausea, vomiting, diarrhea, and lethargy. Two DLT were observed: supraventricular tachycardia and vomiting, but the MTD was not reached. The PK profile shows rapid absorption, with a Tmax of 2–4 hrs, and a dose-dependent increase in systemic exposure over the 15–90 mg dose range. Disease stabilization for ≥4 cycles has been observed. Conclusions: ZK304709 is rapidly absorbed and has been tolerated on this schedule at doses up to 180 mg qd. The MTD has not been reached, and enrolment is ongoing. These preliminary data demonstrate that oral delivery on this schedule of an agent that inhibits both cell cycle and angiogenesis is feasible. [Table: see text]
Randomized, double-blind, vector-controlled study of targeted immunotherapy in patients (pts) with hormone-refractory prostate cancer (HRPC)
Authors: Kantoff P. W. , Glode L. M. , Tannenbaum S. I. , Bilhartz D. L. , Pittman W. G. , Schuetz T. J. 
Published: March 2020

2501 Background: Therapeutic vaccines for prostate cancer have yielded encouraging data in uncontrolled Phase 1 and 2 studies. PROSTVAC-VF comprises 2 recombinant viral vectors each containing genes encoding the prostate-specific antigen (PSA) gene modified to optimize antigen presentation in HLA-A2+ pts and 3 T-cell costimulatory molecules (B7.1, LFA3, and ICAM-1 [TRICOM]). These vectors are administered in a heterologous prime-boost regimen with concurrent low-dose GM-CSF to enhance recruitment of antigen-presenting cells to the immunization site. Here we report results of a Phase 2 study in pts with metastatic HRPC. Methods: In this randomized, double-blind, controlled study, pts were randomized 2:1 to receive either PROSTVAC-VF plus GM-CSF or Control (empty vectors plus GM-CSF placebo) for 24 weeks. Eligible pts had rising PSA despite castrate testosterone levels and measurable, asymptomatic or non-narcotic-dependent metastases (positive bone scan or lymph node metastases on abdominal-pelvic CT scan). The primary endpoint is progression-free survival (PFS), with progression defined as appearance of new lesions on bone scan or RECIST-defined progression of nodal metastases. The planned sample size was 120 pts. The study was designed to detect a difference of 38% vs 12% PFS at Week 24 with a 2-sided α of 0.05 and 80% power. An independent Data Monitoring Committee evaluated safety data quarterly. Results: 125 pts were enrolled. Demographics are available for 122 pts (mean age, 73.3 years [range, 52–94]; ∼11% African American). Common adverse events (AEs) in 106 evaluable pts (blinded as of Jan 2006) included immunization site reactions (73%), fatigue (26%), fever (14%), and nausea (13%). The majority were of Grade 1/2 severity. Serious AEs attributed to immunization included 1 thrombotic thrombocytopenic purpura (TTP) event. Conclusions: A large, randomized, controlled study of therapeutic immunization with PROSTVAC-VF in 125 pts with metastatic HRPC has been completed. The therapy is well tolerated and findings are consistent with Phase 1 results, but also included a single case of TTP. Full efficacy data collection is ongoing. [Table: see text]
A phase II study of the efficacy and toxicity of alemtuzumab for the therapy of human T cell lymphotrophic virus-1 (HTLV-1)-associated adult T-cell leukemia/lymphoma (ATL)
Authors: Sharma K. , Janik J. , O’Mahony D. , O’Hagan D. , Gao W. W. , Wharfe G. H. , Cranston B. E. , Waldmann T. A. , Morris J. C. 
Published: March 2020

2535 Background: HTLV-1-associated ATL is an aggressive lymphoproliferative disorder with limited effective therapy. Alemtuzumab is a humanized monoclonal antibody directed against CD52. High levels of CD52 are expressed on the surface of ATL cells. Preclinical studies in the MET-1 mouse model of ATL showed alemtuzumab to be highly active. Methods: A single institution open-label phase II study examining the response and toxicity of alemtuzumab in patients with ATL. Eligibility criteria: HTLV-1-associated ATL (chronic, acute and lymphoma type), ≥10% CD52+ malignant cells, measurable disease, age ≥18 years, AGC ≥1000/μL, platelets ≥50,000/μL, adequate physiologic status and informed consent. Results: Ten (10) patients, 6 with leukemia, 4 with lymphoma, 8 Afro-Caribbean, 1 African-American and 1 Japanese, 7 women, 3 men, median age 49 years (range, 36–62), all having received previous treatments including CHOP (7), other monoclonal antibodies (5), radioimmunotherapy (2), and radiation (1), median WBC 48,500/μL (leukemia Pts.) received alemtuzumab standard induction followed by 30 mg 3 times weekly for a minimum of 4 weeks and maximum of 12 weeks. All patients experienced infusion reactions (grade, 1–3) including hypotension, fever, rigors, chills, pruritus and urticaria; however, no patient required discontinuation of treatment. All patients developed grade 4 lymphopenia, and transient cytomegalovirus (CMV) antigenemia. Four (4) patients with leukemia responded (1 CR, 3 PR). No patient with lymphoma responded. Conclusions: Alemtuzumab has antitumor activity in HTLV-1-associated adult T cell leukemia and is well tolerated. Lymphomatous ATL appears unresponsive to alemtuzumab. The reason for this is unknown; however, antibody levels achieved in lymph nodes may be suboptimal. Accrual continues. No significant financial relationships to disclose.
An anti-CD40 activating antibody induces dendritic cell maturation and promotes autologous anti-tumor T cell responses in an in vitro mixed autologous tumor cell/lymph node cell model
Authors: Hunter T. B. , Gladue R. P. , Antonia S. J. 
Published: March 2020

2537 Background: CD40-mediated interactions play an important role in the response to a variety of diseases, including cancer. Engagement of CD40 on antigen-presenting cells (APC) by CD40L leads to maturation and upregulation of co-stimulatory molecules, B7.1 and B7.2 (CD80 and CD86), which are requisite in the activation of T cells. Clinical trials involving immunologic interventions have shown clinical responses confirming that the immune system can be harnessed for the treatment of cancer. However, the clinical response rate has been low, signifying the need for new immunotherapeutic strategies. To this end, an agonist antibody specific for CD40 has been developed and is being evaluated as a potential anti-cancer agent. Methods: The activation capacity of anti-CD40 antibody CP-870,893 was analyzed by performing flow cytometric analysis of APC maturation markers following incubation of monocyte derived dendritic cells (DC) with the antibody. IL-12 and macrophage inflammatory protein-1α (Mip1 α) secretion were also analyzed. The effect of the antibody on anti-tumor T cell responses was tested in an autologous human model consisting of tumor cells as stimulator cells and tumor-draining lymph node cells as responders from a series of cancer patients. Results: Cultured DC treated with CP-870,893 consistently display a mature phenotype: robust upregulation of CD80, CD83, CD86 and HLA-DR expression, increased Mip1 α secretion, and the loss of antigen presenting capability. IL-12 secretion was not detected. CP-870,893 also promotes the responsiveness of lymph node derived T cells to autologous tumor, indicated by IFNγ and IL-2 ELISpot. Conclusions: These data demonstrate that CP-870,893 binds to and activates DC. A fully autologous mixed lymph node cell/tumor cell model was used to demonstrate that this activation promotes tumor-specific T cell responses. T cells from the tumor draining lymph node are not responsive to autologous tumor cells, however in the presence of CP-870,893 this unresponsiveness is reversed. These data indicate that CP-870,893 warrants further study as an immunotherapeutic agent in the treatment of cancer. No significant financial relationships to disclose.
Efficacy of intraperitoneal treatment with the trifunctional antibody catumaxomab in patients with GI-tract cancer and peritoneal carcinomatosis: A matched-pair analysis
Authors: Stroehlein M. A. , Gruetzner K. U. , Tarabichi A. , Jauch K. W. , Bartelheim K. , Lindhofer H. , Von Roemeling R. , Heiss M. M. 
Published: March 2020

2544 Background: Peritoneal carcinomatosis (PC) due to GI-tract cancer is an advanced tumor stage with poor survival. At present, no standard therapy has been recommended, as chemotherapy and surgery showed only limited efficacy in affected patients. When applied intraperitoneally (i.p.), the trifunctional antibody catumaxomab could be shown to destroy intraperitoneal tumor cells in patients with malignant ascites due to ovarian cancer. While binding simultaneously to EpCAM (on tumor cells), CD3 (T cells) and, via the Fc region, to Fc gamma receptor 1 and 3 on accessory cells, it induces a complex immunoreaction against epithelial tumor cells. The aim of this study was to investigate clinical efficacy of i.p. catumaxomab therapy in patients with PC compared to a matched control group. Methods: Between 2003 and 2005, 22 patients with PC due to cancer of colon (n=10), stomach (8), pancreas (3) and CUP (1) received treatment with catumaxomab within a phase I study. Treatment consisted of 3 to 4 i.p. applications (10–200 μg) of escalating catumaxomab doses. The survival was compared with patients receiving conventional therapies in a matched-pair analysis regarding sex, age, tumor surgery, chemotherapy, and extent of PC. Patients with existing ileus and clinically significant ascites were not included. Results: Follow up of patients receiving catumaxomab showed a median survival of 12.2 months (range 2–34) after first diagnosis of peritoneal carcinomatosis vs. 9.7 months (range 1–40) in patients with conventional treatment (p=0.005; log-rank). These data will be updated at presentation. Conclusion: Intraperitoneal treatment with the trifunctional antibody catumaxomab may be an attractive option for treatment of patients with peritoneal carcinomatosis due to GI-tract cancer. The convincing results have to be further investigated in clinical phase II/III trials. [Table: see text]