bluuebunny/crossref_metadata_2025_split huggingface dataset:
Phase I and biomarker study of ABT869, a multiple receptor tyrosine kinase inhibitor, in patients with refractory solid malignancies
Authors: Wong C. I. , Thng C. H. , Soo R. , Chen C. S. , Sukri N. , Gupta N. , McKeegan E. , Lee S. C. , Humerickhouse R. , Goh B. C. 
Published: March 2020

3519 Background: ABT869 is an orally administered, potent and specific inhibitor of all VEGF and PDGF family tyrosine kinases, including FLT-3, and c-kit receptors. Methods: A phase I study of ABT869 in patients with refractory solid malignancies was initiated to determine the maximum tolerable dose (MTD) of ABT869 given by continuous once-daily oral dosing; evaluate ABT869 pharmacokinetics; assess pharmacodynamic effects on plasma VEGF and circulating endothelial cells (CECs); evaluate tumor response, including an assessment of microcirculatory parameters DCE-MRI. Dose escalation was planned in dose cohorts of 3 patients each. Treatment periods (TP) were defined as 21 days and tumor assessments were performed using CT scans every 6 weeks. DCE-MRI was done at baseline, day 3 and 14 of the first cycle. Cohort expansion to 6 patients was planned if dose limiting toxicity (DLT) occurred in the first cycle of treatment, and MTD was defined as the dose at which ≥ 2/6 patients experienced DLT. Results: 21 evaluable patients (11 male, 10 female patients median age 58 range 29–76) were treated; 6 at 10mg per day, 12 at 0.25mg/kg/day and 3 at 0.3mg/kg/day. Cycle 1 DLTs included fatigue (grade(G) 3 DLT in 1 patient at 10mg), G3 foot rash, proteinuria and hypertension in 1 patient each at 0.25mg/kg/day (RPTD) and 2 patients with G3 hypertension, including G3 proteinuria in one of these patients, at 0.3mg/kg/day (MTD). Other common treatment-related adverse events at RPTD included asthenia, myalgia, mouth irritation, pneumothorax related to cavitating lung nodule in 2 patients. Pharmacokinetics of ABT869 demonstrated oral clearance of 2.8 ± 1.2 L/h, (mean ± SD, N=16) and half-life of 16.9 ± 5.0 h, with minimal drug accumulation at day 15. 2 PRs were seen in NSCLC patients and stable disease > 4 TPs was observed in 12 patients, with CT scan evidence of cavitation of pulmonary disease and reduced DCE-MRI derived parameters. Mean peak plasma VEGF levels were increased significantly from baseline (p=0.031). CEPs and CECs were reduced in most patients by day 15. Conclusions: 0.25mg/kg/day is the RPTD of ABT869. Modulation of plasma VEGF, CECs and DCE MRI show drug activity consistent with antiangiogenic activity. Promising clinical activity is seen, particularly in NSCLC. No significant financial relationships to disclose.
Phase I study of AZD0530, an oral potent inhibitor of Src kinase: First demonstration of inhibition of Src activity in human cancers
Authors: Tabernero J. , Cervantes A. , Hoekman K. , Hurwitz H. I. , Jodrell D. I. , Hamberg P. , Stuart M. , Green T. P. , Iacona R. B. , Baselga J. 
Published: March 2020

3520 Background: Agents that specifically inhibit the invasive phenotype of cancers are urgently required. AZD0530 is a potent, orally administered inhibitor of Src that has been shown preclinically to prevent phosphorylation of downstream mediators of motility and invasion, paxillin (Pax) and focal adhesion kinase (FAK), with inhibition of metastasis in vivo. Although Src activation is associated with poor prognosis, inhibition of Src activity in human cancers has never been demonstrated. Methods: Patients with cancer received AZD0530 in dose cohorts of 50 mg to 250 mg daily in this 2-part Phase I study. Paired tumor biopsies were acquired for investigation of Src inhibition. Part A defined MTD, toxicity profile and PK. Part B expanded the 50 mg, 125 mg and 175 mg cohorts to characterize changes in phosphorylation of the Src substrates Pax and FAK by evaluating intensity and localization of staining by IHC. Biopsy samples were assigned as pre- or post-AZD0530 treatment by an independent pathology panel blinded to treatment status, and tested for 80% concordance at a 10% alpha. Markers of bone turnover were collected. Results: There were 81 patients evaluable for safety assessment. The median number of prior therapies was 5 (1–27). Part A: DLTs occurred in 3 patients at 250 mg (leukopenia; septic shock (grd5) with renal failure; asthenia) and in 2 patients at 200 mg (febrile neutropenia; dyspnea). Part B confirmed the 50, 125 and 175 mg doses to be tolerable. The mean duration of AZD0530 treatment was 44 days (6–217); 11 patients were treated for longer than 3 months. The pathology panel found consistent modulation of phosphorylation and/or cellular localization of tumor Pax (P=0.067) and FAK (P=0.002) consequent to AZD0530 therapy. There was a dose response trend for reductions in Pax phosphorylation. Bone biomarker and PK data will be presented. Conclusion: For the first time, biomarkers have confirmed inhibition of Src in human cancers. AZD0530 is well tolerated at doses that demonstrate significant inhibition of Src activity. The trend for dose response changes in biomarkers of Src inhibition indicates that the MTD should be taken forward in further development. AZD0530 has a potential role in the prevention of metastases and invasion. No significant financial relationships to disclose.
First-in-human study of AMG 386, a selective angiopoietin1/2-neutralizing peptibody, in adult patients with advanced solid tumors
Authors: Rosen L. S. , Hong D. , Chap L. , Kurzrock R. , Garcia A. , Rasmussen E. , Nguyen L. , Hwang Y. , Storgard C. , Herbst R. S. 
Published: March 2020

3522 Introduction: AMG 386 is a selective angiopoietin1/2-neutralizing peptibody that inhibits angiogenesis by preventing interaction of angiopoietins with Tie2 receptors. This first-in-human study evaluated the safety, pharmacokinetics (PK), and tumor response of AMG 386 in adults with advanced solid tumors. Methods: Patients (pts) in sequential cohorts received weekly IV AMG 386 at 0.3, 1, 3, 10, and 30 mg/kg. Safety assessments were adverse events (AEs), laboratory data, vital signs, ECGs, and anti-AMG 386 antibodies. Tumor response was assessed via RECIST criteria, DCE-MRI, FDG-PET, and volumetric CT. Results: As of Oct. 2, 2006, enrollment is complete with 32 pts (15 men, mean [SD] age 58 [12] years). One dose-limiting toxicity was seen at 30 mg/kg: respiratory arrest likely related to tumor burden, deemed possibly related to AMG 386. Other treatment-related toxicities were all = Grade 2; those observed in = 2 pts were fatigue (n=8), nausea (n=2), and peripheral edema (n=4). PK was dose-linear (mean terminal half-life, 3.1 to 6.3 days). AMG 386 appeared to reach a steady state after 3 doses, with minimal accumulation. Two pts developed binding antibodies to AMG 386; in 1 pt, they disappeared at wk 6. No neutralizing antibodies were seen. Sixteen pts had stable disease (4–52 wks, median 8 wks); 13 had progressive disease; 3 were not evaluable. One pt with ovarian cancer remains active at 52 weeks with 27% tumor shrinkage and investigator-reported reduction in serum CA-125 from 217 U/ml pretreatment to 73 U/ml (wk 4) and 31 U/ml (wk 48). A significant vascular effect (> 20% reduction) was seen by DCE-MRI in 7 of 12 (58%) evaluable subjects. Reduction in SUVmax (FDG-PET) accompanied reduction in IAUC (DCE-MRI) in 5 of 6 evaluable patients. Conclusions: Weekly administration of AMG 386 appeared to be generally well tolerated, with 1 AE > Grade 2 and no reports of the toxicities associated with VEGF blockade (hypertension, proteinuria, bleeding/clotting). Half of pts experienced stable disease; 1 has a sustained minor clinical response accompanied by a biologic response. Further clinical studies of AMG 386 in combination with chemotherapy and other targeted agents are warranted. No significant financial relationships to disclose.
Phase I study of YM155, a first-in-class survivin suppressant, in patients with advanced solid tumors in Japan
Authors: Nakagawa K. , Satoh T. , Okamoto I. , Miyazaki M. , Morinaga R. , Tsuya A. , Hasegawa Y. , Terashima M. , Ueda S. , Fukuoka M. 
Published: March 2020

3536 Background: YM155 is a small molecule expected to induce apoptosis in tumor tissue by suppressing survivin. In the US, a phase I study was conducted with a 168-hr continuous infusion every 3 wks. In Japan, we conducted a similar phase I study to evaluate toxicity profile of YM155 compared with the results of the US study. Methods: The objectives were to determine the MTD, characterize the pharmacokinetics (PK) and observe anti-tumor activity. A standard 3+3 dose escalation scheme was utilized. Results: 34 pts (M/F: 24/10, median age 60, range 26 - 81) were enrolled into 6 dose cohorts [1.8 mg/m2/day (N=3), 3.6 (6), 4.8 (6), 6.0 (8), 8.0 (6), and 10.6 (5)]. 2/5 pts experienced dose-limiting toxicities (DLT) during cycle (C) 1 at 10.6 mg/m2/day (blood creatinine increased (2), lymphocyte count decreased (1)), thus the MTD was 8.0 mg/m2/day. Both pts experienced a DLT (56 yo female, 57 yo male), reached to NCI-CTC grade 2 blood creatinine level at the end of infusion. One of them developed to grade 3 blood creatinine level on day10. They recovered to grade 1 or below in 2 wks without plasma dialysis, so that they continued YM155 infusion decreased to 8.0 mg/m2/day. Renal parameters of them changed in a regular manner, as urine microalbumin increased from day 3 to 7, protein urine from day 6 to 8, and blood creatinine from day 8 to 10. As the other DLT during C1, 1/6 pt experienced AST increased at 6.0 mg/m2/day.. The most frequent AEs were: fatigue (39%), urine microalbumin present (39%), pyrexia (33%), and anemia / haemoglobin decreased (30%). At the MTD, the median YM155 clearance was 39 L/hr with a median steady state concentration of 13 ng/mL and a median terminal half-life of 20 hours. 9/33 pts showed stable disease (SD) and minor tumor shrinkage was observed in 5 of them. One pt (thyroid carcinoma) is ongoing (40 wks) and has had disappearance of pleural effusion. Another patient (malignant fibrous histiocytoma) showed tumor regression in abdominal cavity confirmed by CT scan. Conclusions: YM155, the first survivin suppressant, was well tolerated and the MTD was 8.0 mg/m2/day x 168-hr in Japan. The contribution of YM155 to the treatment of advanced solid tumors should be evaluated in further trials. No significant financial relationships to disclose.
Phase I study of SS1P, a recombinant anti-mesothelin immunotoxin for targeted therapy of mesothelin expressing mesotheliomas, ovarian and pancreatic cancer
Authors: Hassan R. , Bullock S. , Premkumar A. , Kreitman R. J. , Kindler H. , Willingham M. , Pastan I. 
Published: March 2020

3553 Background: Mesothelin, a cell surface glycoprotein, is an attractive candidate for targeted cancer therapy given its limited expression on normal mesothelial cells and high expression in several human cancers including mesothelioma, ovarian and pancreatic cancer. We conducted a phase I study to determine the maximum tolerated dose (MTD), toxicity and pharmacokinetics of SS1P, a recombinant anti-mesothelin immunotoxin. Methods: SS1P given as a 30 minute intravenous infusion was administered to 34 patients (pts) with advanced mesothelioma (n = 19), ovarian (n = 13) and pancreatic (n = 2) cancer. SS1P was administered every other day (QOD) for 6 doses to 17 pts and then QOD for 3 doses to 17 other pts. Results: The initial cohort of 17 pts received SS1P QOD x 6 doses and the MTD was 18 μg/kg/dose. Dose-limiting toxicity (DLT) included grade 3 urticaria (1 pt) and grade 3 vascular leak syndrome (2 pts). To allow further SS1P dose escalation 17 pts were treated on the QOD x 3 schedule and the MTD was 45 μg/kg/dose. The DLT was grade 3 pleuritis and was seen in 2/2 pts treated at a dose of 60 μg/kg and in 1/9 pts treated at a dose of 45 μg/kg. In all cases the pleuritis resolved completely. No grade 4 toxicity was observed. The most common grade 1/2 toxicities included hypoalbuminemia (21 pts), fatigue (17 pts), fever (9 pts) and edema (9 pts). At the MTD of 45 μg/kg the mean Cmax of SS1P was 483 ng/ml and half-life was 466 minutes. Of the 33 evaluable pts treated, 4 had minor response, 18 had stable disease and 11 had progressive disease. Two pts with stable disease had complete resolution of their ascites. A pt with peritoneal mesothelioma had complete resolution of her abdominal ascites, required no further therapy and died of unrelated causes 5 years after SS1P treatment. In the other pt with ovarian cancer there was resolution of abdominal and pelvic ascites that lasted 6 months. Conclusion: SS1P is well tolerated with pleuritis as the DLT at the highest dose level. Anti-tumor activity was noted in a group of heavily pretreated patients. Based on pre-clinical studies that show marked synergy between SS1P and chemotherapy, phase II clinical trials of SS1P in combination with chemotherapy for the treatment of mesothelin expressing cancers will open in 2007. No significant financial relationships to disclose.
Organic arsenic in patients (pts) with advanced solid tumors: Phase-1 results of zio-101 (s-dimethylarsino-glutathione)
Authors: Camacho L. H. , Hong D. S. , Gutierrez C. , Parker C. A. , Purdom M. A. , Tannir N. M. , Moulder S. , Gale R. P. , Schwartz B. , Kurzrock R. 
Published: March 2020

3554 Background: ZIO-101(S-dimethylarsino-glutathione), a novel organic arsenic, is active against multiple cancers in vitro and in animal models. Anti-cancer activity is multifaceted and is mediated by disrupted mitochondrial function, increased reactive oxygen species (ROS) production, modified signal transduction and anti-angiogenesis. Methods: Phase-1 dose finding study to determine maximum tolerated dose (MTD), dose-limiting toxicity (DLT), pharmacokinetics (PK), and toxicities of ZIO-101 in patients with advanced solid tumors. Results: 34 pts (18 M/16 F) received 78–588 mg/m2/d IV for 5 consecutive days every 4 weeks. Median age was 61 (range, 42–79 y). Median N prior regimens was 3 (1–5). Pts had colorectal (N=17; 12 evaluable), renal (N=4), lung (N=3), melanoma (N=2), pancreas (N=2) and others (N=6). Median N of cycles was 2 (range, 1–12). MTD is 420 mg/m2/d and DLT was transient confusion, and ataxia. Fatigue, nausea and emesis were = grade-2. ZIO-101 was otherwise well-tolerated: There are no hematological toxicities and no QTc- prolongation. Five patients had stable-disease 4–12 mo (colorectal [N=3], renal [N=2],). PK studies at 420 mg/m2/d: tmax = 1 h (SD + 0.9), Cmax = 1.06 μg/L (SD ± 0.07 μg/mL), t1/2 = 17.8 h (SD ± 1.4 h) and AUC0- 8 = 25.9 mg·h/L (SD ± 0.8mg.h/L). 1 pt had complete resolution of a brain metastasis (renal) and 1 patient had a substantial decrease of a liver metastasis (pancreas). Conclusions: ZIO-101 was well tolerated. MTD is 420 mg/m2/d and DLT is transient confusion and ataxia. There was observed clinical benefit in five patients. Expansion cohort is ongoing to further test toxicities and antitumor activity. Phase II studies are ongoing. [Table: see text]
Circulating endothelial cells and progenitor cells in metastatic renal cell cancer: Predictive value during anti-angiogenic therapy?
Authors: Farace F. , Vielh P. , Plantade A. , Amsellem S. , Bouaita L. , Vassal G. , Bidart J. M. , Fizazi K. , Escudier B. 
Published: March 2020

3555 Background: Anti-angiogenic therapy has demonstrated efficacy in the treatment of metastatic renal cell carcinoma (MRCC). New surrogate biomarkers are needed to optimize the potential of this novel therapy. Circulating endothelial cell (CEC) and progenitor cell (CEP) measurement has been proposed to monitor anti-angiogenic drug activity and treatment efficiency. Methods: 21 patients (pts) with MRCC were analysed. Among them, 16 were monitored both at baseline and 2 -3 weeks after start of anti-angiogenic treatment (14 pts received sutinimib and 2, nexavar). CECs were measured in one ml erythocyte lysed whole blood by four color flow cytometry (FCM) and identified by a CD45-CD31+CD146+ 7-amino-actinomycin (7AAD)- phenotype. Enumeration of CEC was validated by spiking whole blood with human umbilical vein cells and by immunohistochemical staining of the cell sorted fraction with endothelial markers (Ulex-Europaeus-lectin-1 and Von Willebrand factor). Median CEC value in 20 healthy subjects was 5.5 /ml (range 0–15) wheras this value was 16/ml (range 0–179) in 80 metastatic cancer patients. CEPs were measured by FCM as extremely rare events with a CD45dimCD34+ VEGFR2+7AAD- phenotype. Results: Median MRCC baseline CEC value was 17/ml (range 3 to 101). 16 pts had CEC levels that were two-fold greater than healthy subjects (>10/ml). Preliminary data showed a dramatic drop in CEC levels in patients that responded to therapy. Median baseline CEP value was 0.49% of hematopoietic stem cells (HSC), with ranges from 0.06% to 9% (absolute counts: 10/ml range 1 to 181/ml). Eight patients had CEP values greater than 1% of HSC and all had high tumor burden. Among the 16 pts monitored, all except 2 showed a dramatic increase in CEPs after treatment suggesting that anti-VEGFR2 targeted therapy might induce peripheral accumulation of CEP. Updated data and correlations with prognostic factors and clinical outcome will be presented. Conclusion: During anti-angiogenic therapy, dramatic changes in both CEC and CEP levels were observed. Predictive values of CEC and CEP are currently under evaluation. No significant financial relationships to disclose.
In vivo perspective study about the effects of weekly low dose administration of zoledronic acid (ZA) on angiogenesis
Authors: Santini D. , Vincenzi B. , Battistoni F. , Galluzzo S. , Rocci L. , Uzzalli F. , Venditti O. , Grilli C. , Dicuonzo G. , Tonini G. 
Published: March 2020

3558 Purpose: Recent data have demonstrated in preclinical tumor models an antiangiogenic and antitumor activity of low weekly doses of ZA. As a consequence, the purpose of this study was to confirm these data, evaluating in cancer patients the modifications in angiogenic cytokines levels following repeated weekly low doses of ZA. Experimental Design: 26 consecutive cancer patients with bone metastases treated, for the first time, with four weekly doses of 1 mg of ZA followed by standard doses (4 mg every 28 days) were prospectively evaluated for circulating levels of vascular endothelial growth factor (VEGF) at different time points: just before and after 1, 7, 14, 21, 28, 56 and 84 days following the first disphosphonate infusion. Results: Basal serum VEGF median levels were significantly decreased just after 7 days (-29.7%) (with only one weekly infusion) (P=0.038), This significant decrease of circulating VEGF levels persisted 14(-33.2%), 21 (-39.4%), 28(-31.8%), 56(-33.6%) and 84(-27.9%) days after the first infusion (respectively, P=0.002, P=0.001, P=0.008, P=0.002, P=0.014). Conclusions: This study confirms, for the first time in humans, that weekly low doses of zoledronic acid could have antiangiogenic properties through a significant and long lasting decrease of VEGF serum levels. No significant financial relationships to disclose.
Phase 1 studies assessing the safety, PK, and VEGF-modulating effects of PTC299, a novel VEGF expression inhibitor
Authors: Hirawat S. , Elfring G. L. , Northcutt V. J. , Paquette-Lamontagne N. , Davis T. , Weetall M. , Babiak J. , Miller L. L. 
Published: March 2020

3562 Background: VEGF expression is regulated posttranscriptionally through the 5’- and 3’- untranslated regions (UTRs) of its mRNA. PTC299 is a novel, orally bioavailable, small molecule that acts via the VEGF 5’-UTR to selectively inhibit tumor VEGF production. In multiple preclinical human tumor xenograft models, PTC299 reduces elevated human VEGF levels in tumor and in circulation, decreases tumor microvessel density, and substantially slows tumor growth. With cytotoxic agents or with other antiangiogenics, PTC299 enhances tumor growth delay. Methods: PTC299 safety in animal toxicology studies supported Phase 1 studies in healthy volunteers. The first study was a Phase 1 single-dose (SD) trial. The second study was a Phase 1, multiple-dose (MD) study assessing BID or TID dosing for 7 days. During dose escalations, 8 subjects (4 males, 4 females; 6 PTC299, 2 placebo) per cohort were randomized in a double-blind manner. A fed-fasting crossover was performed in 12 subjects (6 males, 6 females) in the SD study. Subjects underwent clinical observations, laboratory testing, and blood sampling for PK and circulating VEGF. Results: In the SD study, 52 subjects (age range 18–55 years) were enrolled (40 at 5 dose levels and 12 to assess food effects. In the MD study, 32 subjects (age range 31–78 years) were enrolled (24 to BID dosing and 8 to TID dosing). AEs included: headache, dizziness nausea, vomiting, and stomach discomfort (all Grade 1); and diarrhea (Grade 2). No bleeding, clotting, hypertension, or proteinuria occurred. Cmax and AUC increased proportional to dose. There was a ∼40% increase in the Cmax with food, but no change in AUC. Mean PTC299 Cmax and AUC increased by ∼2-fold over 7 days, exceeding target trough plasma concentrations active in xenograft models. A 2-compartment model describes the PK data. Circulating VEGF levels are being assayed. Conclusions: PTC299 is the first drug designed to modulate post-transcriptional control mechanisms to treat human disease. In these initial studies, PTC299 shows safety at plasma exposures associated with preclinical activity and can be taken without regard to food. Final clinical data on dose ranging, safety, PK, and circulating VEGF levels will be presented. Studies of PTC299 in patients with cancer are being initiated. No significant financial relationships to disclose.
AAV-mediated delivery of interferon-β for the treatment of retinoblastoma in preclinical models
Authors: Shih C. , Laurie N. , Holzmacher J. , Davidoff A. , Dyer M. 
Published: March 2020

3565 Background: Interferon-β has anti-tumor properties against a variety of malignancies through direct cytotoxicity as well as immunological effects. In order to circumvent limitations of IFN-β therapy, we have developed an adeno-associated viral gene therapy approach to deliver IFN-β directly to tumors. In this study, we tested the efficacy of AAV mediated delivery of IFN-β in preclinical retinoblastoma models. Retinoblastoma is an ideal candidate for gene-therapy based anti-cancer treatments because viral infection and IFN-β delivery can be contained within the ocular environment thereby minimizing systemic toxicity. Methods: Retinoblastoma cell lines Weri and Y79 were treated in vitro with recombinant human Interferon-β and then subjected to Viacount assays, Nexin apoptosis assays, FACS cell cycle analysis, and immunolabeling for proliferation (BrdU) and apoptosis (caspase and TUNEL). An orthotopic Xenograft retinoblastoma rat model with luciferase reporter were established and treated with single subconjunctival injection of AAV-IFN-β gene therapy. Xenogen in vivo imaging was used to follow tumor volume. Blood and tissue samples (ELISA) were obtained to determine IFN-β levels. Results: Weri and Y79 cells showed maximum reduction in viability at 500 IU/ml and 2500 IU/ml respectively. Weri response was found to be cell death by Caspase and TUNEL assay. Y79 response was found to be due to suppression of proliferation as measured by BrdU incorporation and cell cycle analysis. In the retinoblastoma xenograft model there was no increase in tumor volume by serial in vivo imaging compared to control animals. Stable levels of IFN-β were maintained at 20 ng/ml >6weeks following injection. Plasma levels were undetectable 42 days following treatment. Conclusions: Retinoblastoma cell lines exhibit pleiotropic responses to IFN-β consistent with previous studies. Intravitreal injection of AAV-IFN-β resulted in efficient retinal infection and sustained IFN-β production. Viral spread outside of the eye was not detected. Using our retinoblastoma xenograft model we found that intravitreal injection of AAV-IFN-β had a potent anti-tumor effect in vivo. These data suggest that AAV mediated delivery of IFN-β may provide a complementary approach to systemic chemotherapy. No significant financial relationships to disclose.