bluuebunny/crossref_metadata_2025_split huggingface dataset:
Vaccination of stage IV melanoma patients with dendritic cells generated ex vivo with type I interferon and loaded with heat-treated killed allogeneic melanoma cells—Preliminary report from the phase II clinical trial
Authors: Palucka A. , Nemunitis J. , Weber J. , Ueno H. , Auditore-Hargreaves K. , Fay J. , Banchereau J. 
Published: March 2020

2582 Background: We have previously demonstrated in phase I clinical trial treating 20 patients with metastatic melanoma that dendritic cells (DCs) loaded with killed allogeneic tumor cells can elicit immune and clinical responses. In that study DCs were generated from monocytes with GM-CSF and IL-4 and activated with a combination of TNF and soluble CD40 ligand. Two patients who had failed previous therapy including DTIC, achieved durable objective clinical responses, one CR and one PR lasting ≥ 20 months. We describe here the development of a high-throughput method for generating DC vaccines with improved immunogenicity and preliminary data from their evaluation in a Phase II trial in metastatic melanoma. Methods: We have initiated a phase II clinical trial (IRB #005–065; BB-IND #12339) enrolling patients with stage IV melanoma who failed first line therapy with DTIC and/or temozolomide with or without IL-2. Patients will receive seven injections of an autologous DC vaccine generated from monocytes by culturing with GM-CSF and Type I interferon and loaded with heat-treated and killed allogeneic Colo829 melanoma cells. Vaccine is generated in a closed system and stored frozen. Patients are vaccinated over 18 weeks. The trial is based on an initial toxicity evaluation in the first 10 patients on top of a 2-stage response rule - 1/19 to continue and 5/30 to accept. The trial is expected to accrue a total of 32 subjects. The primary end-points of this trial are the rate of objective clinical response and the safety/feasibility of the vaccination preparation. Results: To date seven patients were enrolled and begun vaccinations. Vaccine has been successfully generated for all enrolled patients. Thus far, a total of 20 vaccinations have been administered. Vaccinations were safe and tolerable. [Table: see text]
Multi-targeted inhibition of the epidermal growth factor (EGFR) and vascular endothelial growth factor receptor (VEGFR) pathways: A phase I study of cetuximab (C), erlotinib (E), and bevacizumab (B) in patients with solid tumors
Authors: Preston G. G. , Calvo E. , Papadopoulos K. , Patnaik A. , Mita A. , Sarantopoulos J. , Mita M. , O’Rourke P. , Takimoto C. , Tolcher A. 
Published: March 2020

3005 Background: Complex interrelationships exist between the EGFR and VEGFR pathways. EGFR activation elicits cell proliferation, and downstream effects increase expression of VEGF. In renal cell carcinoma, mutations increase hypoxia inducible factor-1alpha, stimulating VEGF and transforming growth factor expression. Moreover, there is additive tumor inhibition from combined EGFR targeting with C, and a tyrosine kinase inhibitor. To maximally inhibit EGFR, and then inhibit downstream VEGFR activity, this phase I study was initiated to determine the maximum tolerated dose (MTD) of E with a fixed dose of C, and then the MTD of B with combined E and C in patients with advanced malignancies. Methods: Patients with advanced malignancies likely to express EGFR were entered in part 1 to daily oral E (starting at 100mg, planned initially to increase to 150 mg), with fixed dose C (400 mg/m2 loading and 250 mg/m2 IV weekly). Once the MTD was determined for E in combination C, part 2 incorporated the addition of escalating doses of B (5 mg/kg IV every 2 weeks, to increase to 10 mg/kg) to the combination of E and C. Results: 27 patients were entered and received 84 courses over 3 dose levels. In part 1 grade 3 rash occurred in 2 patients at E at 100 mg daily, and the MTD of E for this combination was 50 mg daily with standard dose C (12 patients treated). Other adverse events included rash, diarrhea, hypomagnesemia, and nausea. Part 2: B at 5 mg/kg IV q14 days can be added to the MTD of E with C, with additional non-dose limiting toxicities of headache, proteinuria, and hypertension. Durable stable disease has been observed in 4 patients with metastatic disease for 7 (sqaumous cell); 10+, 12, and 12+ (renal cell) months. Conclusions: The MTD for E combined with standard C is 50 mg daily. B at 5mg/kg can be combined safely with this combination and dose escalation is ongoing. [Table: see text]
HGS-ETR2—A fully human monoclonal antibody to TRAIL-R2: Results of a phase I trial in patients with advanced solid tumors
Authors: Patnaik A. , Wakelee H. , Mita M. , Fitzgerald A. , Hill M. , Fox N. , Howard T. , Ullrich S. , Tolcher A. , Sikic B. 
Published: March 2020

3012 Background: HGS-ETR2 is a fully-human high-affinity monoclonal antibody that is agonistic to the Tumor Necrosis Factor-Related Apoptosis-Inducing Ligand Receptor 2 (TRAIL-R2, DR5). TRAIL-R2 is expressed more widely on the surface of tumor cells than normal cells; binding of HGS-ETR2 to TRAIL-R2 leads to activation of the extrinsic apoptosis pathway. HGS-ETR2 shows anti-tumor activity at doses ≥ 0.3 mg/kg in xenograft models, both as a single agent and in combination with chemotherapeutic agents. Methods: This phase 1, dose-escalation study assessed the safety, tolerability, pharmacokinetics and immunogenicity of HGS-ETR2 administered IV every 14 days in patients with advanced solid tumors. Patients received HGS-ETR2 until disease progression or unacceptable toxicity. Tumor measurements were repeated every 2 months. Results: To date, 31 patients have received 167 courses of HGS-ETR2 over 5 dose levels: 0.1, 0.3, 1.0, 3.0 and 10.0 mg/kg q14 days. The majority (26 of 31) received at least 4 courses. One patient experienced a dose-limiting toxicity of grade 3 hyperamylasemia at the 10 mg/kg dose level. The event was determined to be possibly related to HGS-ETR2 and also possibly related to a nutritional supplement. Stable disease was achieved in 10 patients for 4 to 16 cycles. One patient with chemotherapy-refractive Hodgkin’s disease had a tumor regression of abdominal disease. HGS-ETR2 pharmacokinetics were linear up to 10 mg/kg. At the 10 mg/kg dose, the pharmacokinetics were characterized by a mean (SD) t1/2β of 11 (4) days, CL of 6.0 (0.7) mL/day, and V1 of 47 (8) mL/kg, slightly larger than the plasma volume. The 1.8-fold larger Vss of 85 (27) mL/kg indicates that HGS-ETR2 distributes outside the plasma compartment. Human anti-human antibody formation has not been detected. Conclusions: HGS-ETR2 can be safely administered every 14 days at doses up to and including 10 mg/kg. Further evaluation of HGS-ETR2 is planned, including studies of HGS-ETR2 in combination with chemotherapeutic agents. [Table: see text]
A phase I safety and pharmacokinetic (PK) study of recombinant Apo2L/TRAIL, an apoptosis-inducing protein in patients with advanced cancer
Authors: Herbst R. S. , Mendolson D. S. , Ebbinghaus S. , Gordon M. S. , O’Dwyer P. , Lieberman G. , Ing J. , Kurzrock R. , Novotny W. , Eckhardt G. 
Published: March 2020

3013 Background: Recombinant human Apo2L/TRAIL (rhApo2L) is the only dual pro-apoptotic receptor agonist that directly activates both pro-apoptotic receptors (DR4 & DR5). RhApo2L selectively induces apoptosis (programmed cell death) in a variety of cancer cells, while sparing most normal cells in preclinical models. RhApo2L is being co-developed by Genentech and Amgen as a targeted therapy for solid tumors and hematologic malignancies. The present study was designed to assess the safety and PK of intravenous rhApo2L administered for the first time to humans, comparing safety in patients with liver metastasis to those without. Methods: RhApo2L was administered to patients with advanced solid tumors or NHL for 5 consecutive days every three weeks up to 8 cycles at dose levels of 0.5, 1.5, 4, 8, and 15 mg/kg. Patients without liver metastasis were treated before patients with liver metastasis in a staggered fashion. Results: Fifty-one adult patients have currently been enrolled and treated through 15 mg/kg. Of 36 patients with available data, the most common diagnoses were colorectal, melanoma, lung, and ovarian cancers. After 586 administered doses, there were no dose-limiting toxicities or clearly attributable toxicities. Thirty-two patients had at least one post-baseline tumor assessment with 17 (53%) having stable disease, and 13 (41%) with progression. One patient with a chondrosarcoma had a confirmed, objective partial response at 8 mg/kg. No anti-Apo2L antibodies have been detected. PK results will be presented separately. Conclusions: RhApo2L is safe and well tolerated up to 15 mg/kg. Enrollment is continuing at 8 mg/kg for expanded safety data and further dose optimization. Contribution to the standard treatment of advanced solid tumors and hematologic malignancies should be evaluated in randomized trials. [Table: see text]
Safety and antitumor activity of AMG 706 in patients (pts) with thyroid cancer (TC): A subset analysis from a phase 1 dose-finding study
Authors: Boughton D. , Rosen L. , Van Vugt A. , Kurzrock R. , Eschenberg M. , Wiezorek J. , Ingram M. , Wang D. , Stepan D. , Herbst R. S. 
Published: March 2020

3030 Background: AMG 706 is an investigational, oral, small molecule multi-kinase inhibitor with both antiangiogenic and direct antitumor activity that selectively targets VEGF, PDGF, and Kit receptors. From a phase 1 study (Rosen ASCO 2005; Herbst EORTC 2005), encouraging antitumor activity was seen in pts with TC. In this analysis, we report on the TC subset from the study. Methods: Pts with refractory solid tumors received oral AMG 706 QD (50, 100, 125, 175 mg) or BID (25 mg) intermittently or continuously for 28-day cycles. Study objectives were to assess safety, establish the maximum tolerated dose (MTD), and generate pharmacokinetic profiles of AMG 706 in these pts. Tumor response (modified RECIST) was evaluated at wk 8 and Q12W thereafter. Data from Oct 2005 were analyzed. Results: In this study, 7 of 71 pts enrolled had TC. Baseline demographics for this subset were 4 W/3 M, median (range) age of 58 (41, 78) yrs, ECOG 1 (71%), and all had stage IV disease. Histologies were papillary (3: PTC), follicular (1; FTC), Hürthle cell (1), anaplastic (1), and medullary TC (1; MTC). All pts received prior external radiotherapy, radioiodine, chemotherapy, and/or surgery. Initial doses of AMG 706 were 125 mg and 175 QD and 25 mg BID. The MTD for the study was 125 mg QD. Median (range) time on treatment for the TC pts was 141 (14, 564) days. Treatment-related adverse events are summarized ( table ). Best objective responses were 3 pts with partial response (PR), 3 with stable disease (SD), and 1 with progressive disease. PR was seen in pts with MTC, PTC and FTC. Two pts with PR did not have confirmation of response (1 had a PR during the last assessment). The 3 pts with PR received AMG 706 for 338, 366, and 564 days; 2 pts are still receiving AMG 706. Time to response for these 3 pts were 210, 217, and 304 days. Conclusion: In patients with TC, AMG 706 appears to be relatively well tolerated and displays promising antitumor activity for some pts. Based on these favorable findings, a phase 2 study of AMG 706 for the treatment of advanced TC is ongoing. [Table: see text] [Table: see text]
VEGFR2 blockade in patients with solid tumors: Mechanism of hypertension and effects on vascular function
Authors: Steeghs N. , Hovens M. M. , Rabelink A. J. , Op ’t Roodt J. , Matthys A. , Christensen O. , Gelderblom H. 
Published: March 2020

3037 Background: Hypertension is the most common side effect in trials with inhibitors of vascular endothelial growth factor (VEGF) signaling, although the underlying pathophysiology is unclear. As the use of anti-VEGF therapy is increasing, hypertension and related serious adverse events are likely to become more important. Methods: To better understand this pathophysiology,blood pressure and vascular function parameters were assessed in this substudy of a phase I trial in patients with advanced solid tumours treated with BAY 57–9352, an oral VEGF receptor 2 (VEGFR2) inhibitor. Blood pressure, flow-mediated dilatation (FMD), nitroglycerin-mediated dilatation (NMD) and pulse-wave velocity (PWV) were measured at baseline and after 5 weeks of daily treatment in 10 patients. Patients were spread out over different cohorts, taking different dosages of study drug. Results: Mean systolic blood pressure increased from 129.0 mm Hg to 139.4 mm Hg after 5 weeks of treatment (difference 10.4 mm Hg; 95% confidence interval (CI) 5.0–15.7 mm Hg; p=0.002). Mean diastolic blood pressure increased from 80.9 to 87.4 mm Hg (difference 6.5 mm Hg; 95% CI 1.7–11.3; p=0.013). Endothelium-dependent vasodilatation (FMD) decreased from 5.6% to 3.0% (95% CI 1.1–3.9%; p=0.003). NMD, indicating endothelium-independent vasodilatation, also decreased from 12.9% to 7.7% (95% CI 2.7–7.6%; p=0.001). Arterial stiffness (PWV), increased from 9.4 m/s to 10.3 m/s (p=0.07). Conclusions: Inhibition of VEGFR2 significantly increases systolic and diastolic blood pressure. As VEGF enhances endothelial nitric oxide (NO) synthetase activity, the clear decrease in FMD could be explained by reduced bioavailability of NO. The decrease in NMD may be a direct effect of VEGFR2 inhibition on vascular smooth muscle cells. However, a more likely hypothesis for these profound vascular effects is a reduced number of microvessels (i.e. rarefaction). As the microcirculation is largely responsible for peripheral resistance, the rarefaction associated with VEGFR2 inhibition is likely to increase peripheral resistance and lead to hypertension. [Table: see text]
Phase I study of an anti-angiogenic agent with a novel mechanism of action E7820: Safety, pharmacokinetics (PK) and pharmacodynamic (PD) studies in patients (pts) with solid tumors
Authors: Mita M. M. , Mita A. C. , Ricart A. , Rodon J. , Till E. , Okereke C. , Desai P. , Zang E. , Rowinsky E. K. , Takimoto C. 
Published: March 2020

3048 Background: E7820 is a first-in-class oral antiangiogenic sulfonamide that inhibits alpha-2 integrin expression, endothelial cell proliferation and is active against human breast and pancreatic cancer xenografts. Methods: The objectives of the study were to evaluate the safety, tolerability, to determine the maximum tolerated dose (MTD) to characterize the PK behavior, to assess PD markers and to explore the antitumor activity. Results: Thirty pts (18 male/12 female; age range 40–83) received E7820 at doses ranging from 10 to 200 mg daily continuously, in a 28 day cycle. A total of 93 cycles were administered (range 1–15); 4 pts underwent intrapatient dose escalation. Dose-limiting toxicities (DLT) at 100 mg/day included grade (gr) 3 elevated liver enzymes and gr 3 hemoptysis. At the 200 mg dose level, 2 pts experienced hematological toxicity, including gr 4 thrombocytopenia and neutropenia. One of these patients with cervical cancer and a vaginal fistula had gr 4 thrombocytopenia, neutropenia and gr 3 anemia with a fatal bleed from her pelvic tumor. Other gr 3/4 adverse events included: nausea, vomiting, fatigue, hypoxia, chest pain, abdominal pain, ileus, anemia, neutropenia, hypoalbuminemia, elevated transaminases and alkaline phosphatases. Disease stabilization beyond cycle 4 was observed in 6 pts, with 3 lasting for 6+ months. Tmax ranged from 1.3–5.3 hr and the t1/2 is 5.7 to 11.9 hr. Cmax and AUC increased dose proportionaly up to 70 mg, however accumulation was seen at 200 mg. At higher doses (70–200 mg) plasma concentrations exceed levels active in preclinical models in vivo. Preliminary analysis of alpha-2 integrin expression showed marked (∼50%) and sustained decreases beyond day 28 in 3 of 4 pts at 200 mg, while moderate (<30%) and less consistent decreases were observed in 2/3 and 3/6 pts at 70 mg and 100 mg dose levels, respectively. No changes in integrin levels were observed at E7820 doses < 40 mg. Conclusions: Up to 100 mg/day E7820 has a good safety profile in pts with solid malignancies. MTD was established at 100 mg/day. Patient treatment and PD analyses are ongoing. [Table: see text]
Myocardial HER2 expression with 111In-DTPA-trastuzmab scan in patients shortly after anthracycline treatment
Authors: Perik P. J. , Lub-De Hooge M. N. , Jager P. L. , De Korte M. A. , Gietema J. A. , Van der Graaf W. T. , Van Veldhuisen D. J. , Sleijfer D. T. , De Vries E. G. 
Published: March 2020

3057 Background: The monoclonal antibody trastuzumab, apart from antitumor effect, can induce cardiotoxicity, particularly when combined with anthracyclines. Myocardial HER2 upregulation may serve, transiently, as a compensatory mechanism induced by cardiac stress. Previously we showed in a xenograft model that 111In-DTPA-trastuzumab scintigraphy can detect HER2 positive lesions (Br J Pharmacol 2004;143:99–106) but that myocardial 111In-DTPA-trastuzumab uptake was found in only 1 of 17 anthracycline-pretreated HER2-positive metastatic breast cancer patients (ESMO 2004#50). This low number may be related to the long interval between anthracycline administration (median 11 months) and performed scan in these patients. To evaluate whether myocardial HER2 expression is induced by anthracyclines, we performed 111In-DTPA-trastuzumab scans in patients shortly after anthracycline treatment. Methods: Patients who completed 4–6 cycles of anthracycline-based chemotherapy (< 3 weeks after last dose) underwent gammacamera imaging 48 and 96 h after iv administration of 150 MBq 111In-DTPA-trastuzumab (5mg). Results: 10 anthracycline-treated patients, 8 as adjuvant breast cancer treatment and 2 for metastatic sarcoma have been enrolled. Myocardial 111In-DTPA-trastuzumab uptake was observed in 5/10 anthracycline-treated patients who all were without symptomatic cardiac dysfunction. Conclusions: Shortly after completion of anthracycline treatment myocardial HER2 overexpression was detectable in 50% of the patients. This may be a transient phenomenon. 111In-DTPA-trastuzumab scan after anthracycline treatment prior to adjuvant trastuzumab may identify patients more susceptible for trastuzumab-induced cardiotoxicity. This important observation may add to optimal timing of trastuzumab therapy i.e. when HER2/neu expression in the heart is negative (again). [Table: see text]
Relationship between tumor blood flow and serum albumin levels: A positron emission tomography study
Authors: Koetz B. , Bruce J. , Price P. 
Published: March 2020

3058 Background: Positron emission tomography (PET) is increasingly used to aid development of drugs targeting the tumor vasculature. Reduced serum albumin levels lead to a decrease in plasma colloid osmotic pressure, reducing the effective intravascular volume. This study examined the relationship between serum albumin levels and tumor perfusion parameters evaluated with PET. Method: PET perfusion studies using oxygen-15-labeled water (H215O) were performed as part of clinical trials in 18 patients with advanced solid tumors. Regional tumor blood flow (mlblood/min/mltissue) and volume of distribution of water (Vdwater;ml/mltissue), an indicator of the fraction of tissue participating in the exchange of water, were measured prior to any intervention and related to serum albumin levels. Two-tailed Pearson’s correlation coefficient was used for statistical analysis. Results: Serum albumin levels ranged from 19 to 44g/l (median 32g/l). Regions of interest were drawn in 7 renal cell cancers, 5 liver metastases, 2 hepatomas, 2 para-aortic lymph node metastases, one mesenteric and one pelvic mass. Tumor blood flow ranged from 0.13 to 1.67mlblood/min/mltissue (median 0.47mlblood/min/mltissue) and tumor Vd water from 0.39 to 1.11ml/mltissue (median 0.69ml/mltissue). A significant correlation between serum albumin level and tumor blood flow (r=0.51, P=.031) could be demonstrated, whereas Vdwater was independent of albumin levels (r=0.29, P=.21). Conclusions: This study demonstrates that tumour blood flow is related to serum albumin levels. Changes in serum albumin levels need to be considered when assessing effects on tumor blood flow with treatments targeting the tumor vasculature, particular if given over several weeks. The fraction of perfused tissue may more accurately assess the vascular effects of cancer treatments. If correction of serum albumin levels could be used for therapeutic benefit will require further research. No significant financial relationships to disclose.
Phase Ib pharmacokinetic (PK) and pharmacodynamic (PD) study to define the optimal dose for combining the mTOR inhibitor AP23573 with capecitabine (CAPE)
Authors: Perotti A. , Maur M. , Viganò L. , Gallerani E. , Angst R. , Albanell J. , Sessa C. , Laliberte R. , Marsoni S. , Gianni L. 
Published: March 2020

3065 Background: AP23573 is a novel mTOR inhibitor with anti-tumor activity in Phase1 and 2 trials. In vitro, AP23573 is at least additive with chemotherapy agents including 5FU. CAPE is activated to 5FU by thymidine phosphorylase which may be highly expressed in tumors and correlates with progression through angiogenic mechanisms controlled by mTOR. Given the potential for a positive interaction, this trial studied the combination of AP23573 and CAPE in adult patients with solid tumors. Methods: Starting doses were: AP23573 25 mg i.v. on Days 1, 8, and 15 of a 28-day cycle, and CAPE 1650 mg/m2 p.o. daily on Days 1–14. Planned PK and PD studies include analysis of plasma VEGF, PBMC, skin, and tumor samples for effects on pathways associated with mTOR and on the metabolism of CAPE and fluoropyrimidines. Dose limiting toxicity (DLT) was defined as: febrile neutropenia; neutrophils <500x106/L for ≥ 5 days; ≥ Grade 3 (CTC) thrombocytopenia; non-haematological toxicities ≥ Grade 2 (diarrhea, cardiac or renal); or missing two consecutive weekly doses due to any toxicity. Results: 15 patients have been treated. Three dose levels of weekly AP23573 (25, 37.5 and 50 mg) were completed without DLT. Treatment-related toxicity was mostly mild or moderate (≤ grade 2), with mucositis/stomatitis the most frequent. Anti-tumor activity included a partial response in a case of endometrial cancer, and stable disease > 4 months in 3 cases (1 renal, 1 uterine and 1 head & neck cancer). AP23573 did not affect the PK of CAPE or 5FU but a trend toward a decreased exposure to the catabolite 5-FuH2 was apparent in the presence of AP23573. In keeping with this observation, the activity of dihydro-pyridine-dehydrogenase gradually decreased to 60% of that before AP23573. This decrease was not associated with reduced tolerability. Conclusions: The combination of AP23573 with CAPE is safe with initial indications of anti-tumor activity. This is the first description of a feasible combination of an mTOR inhibitor with an anti-metabolite. Additional dose levels of AP23573 (75 mg) and CAPE (1850 mg/m2/day) are ongoing and PK and PD studies are continuing. [Table: see text]