bluuebunny/crossref_metadata_2025_split huggingface dataset:
In vivo synergy combining oxaliplatin with AVE8062, a vascular-disrupting agent
Authors: Demers B. , Vrignaud P. , Bissery M. 
Published: March 2020

13074 Background: AVE8062 is a synthetic, water-soluble compound, analog of Combretastatin A4, currently in Phase I clinical trials. It inhibits tubulin polymerization through binding to the colchicine site of tubulin. In vivo, it induces rapid tumor blood flow shutdown and necrosis, leading to tumor regressions (Proc AACR, 2002). Previously (Proc AACR, 2003), we reported a high synergy resulting from the combination of AVE8062 with either cisplatin or carboplatin in a preclinical in vivo model. We report here the combination data of AVE8062 with oxaliplatin. Methods: A 3-arm dose-response study was performed comparing the single agents and their combination. Synergy was defined as a log cell kill (lck) of at least 1 log superior to the lck of the best single agent. The AVE8062 / oxaliplatin simultaneous combination was evaluated in female BALB/c mice bearing advanced stage (250mg) SC murine colon C51 adenocarcinoma. Drugs were administered IV with 2 intermittent injections, 4 days apart. The combination arm was evaluated over 7 dose levels. Results: At the Highest nontoxic dose (HNTD - 58 mg/kg/inj), AVE8062 was found active: 0.9 lck, 1/5 partial regression (PR) and no complete regression (CR). At the HNTD (7 mg/kg/inj), oxaliplatin was found highly active [5.8 lck, 5/5 CR, no tumor free survivors (TFS)]. The HNTD for the combination (58 mg/kg/inj of AVE8062 with 7 mg/kg/inj of oxaliplatin) was well tolerated with 11.7% body weight loss at nadir. The combination was highly active over the 2 highest dose levels with TFS on day 148 post tumor implantation (4/6 TFS at combination HNTD and 6/6 TFS at 80% HNTD). A high antitumor activity was maintained at 60% HNTD (5.9 lck, 6/6 CR and no TFS). The lowest dose tested, corresponding to 1/10 of the HNTD fractions, was found active with a lck of 1.0 and no regression. Conclusions: The combination of AVE8062 with oxaliplatin was found highly synergistic (superior activity than either of the single agents alone). The combination was well tolerated with a combination toxicity index of 2, indicating that there was no overlap in host toxicity. These data provide a good rationale to perform Phase I combination trials combining AVE8062 with oxaliplatin. [Table: see text]
Model development of human sarcomas for identification and validation of new targets
Authors: Bagley R. G. , Rouleau C. , Weber W. , Cao X. , Teicher B. A. 
Published: March 2020

13080 Background: Soft tissue sarcomas are malignant tumors that can develop from a variety of tissues. There is a lack of targeted therapies directed specifically against sarcomas with surgery, radiation, and chemotherapy being the standard of care. By employing multiple strategies, new targets that may advance sarcoma therapy can be identified. Methods: Profiling of secreted cytokines that may drive tumor growth was performed on cell lines representing osteosarcomas, liposarcomas, fibrosarcomas, and rhabdomysarcomas. Of 27 cytokines analyzed from cultured media, the following were most highly expressed: IL-6, IL-8, IL-12p40, SDF-1, and MCP-1. Results: Results were compared against gene expression data from publicly available oligonucleotide microarrays derived from human tumors. Ewing’s sarcoma and rhabdomysarcoma samples confirmed higher expression levels of VEGF. Further analysis of array data from 16 classes of sarcomas and 181 tumors indicated that IL-7 was more predominantly expressed than IL-6 and IL-8. To evaluate efficacy of novel agents, xenograft models were established using human cell lines A673 rhabdomyosarcoma and SW872 liposarcoma. Tumor growth and response to therapy was characterized. Paclitaxel (75 mg/kg, days 7, 9, 11) delayed tumor growth for about one week following treatment in both models, however only SW872 liposarcoma tumors responded after dosing with anti-angiogenic agent, Avastin (5 mg/kg, days 4, 7, 11, 14, 17, and 21). Conclusions: In addition to killing cancer cells, destabilization of the vasculature/stroma may be beneficial. Immunohistochemical (IHC) analysis was performed on sarcoma tumors from the clinic. CD31 and SMA staining identified vasculature and stromal regions. Subsequent to identification of novel targets specific to sarcomas, IHC methods can further define localization of antigens between various tumor components. A variety of techniques are being utilized in order to recognize new targets in sarcomas. Cell-based assays and preclinical models are incorporated into the drug development pathway to evaluate novel drugs. Analysis of differential gene expression between tumor types and amongst sarcoma subtypes will be essential in identifying which patient population will gain the greatest benefits from targeted therapies. [Table: see text]
A phase I trial of erlotinib (E), cisplatin (C) and radiotherapy (RT) for patients with locally advanced squamous cell cervical cancer
Authors: Ferreira C. G. , Salgado M. , Lima R. , Viegas C. , Small I. A. , Fontão K. , Herchenhorn D. , Madeira D. M. , Martins R. G. , Rodrigues A. N. 
Published: March 2020

13081 Background: Pre-clinical data indicates that inhibition of epidermal growth factor receptor (EGFR) potentiates the effect of RT. This phase I trial aims to determine the maximal tolerated dose (MTD) of erlotinib, an oral EGFR tyrosine kinase inhibitor, when administered concurrently with standard chemoradiation (CRT) for cervical cancer. Methods: In a modified Fibonacci design, two cohorts of three patients received escalating doses of E (50 mg/100 mg) one week before and combined with C (40 mg/m2, weekly, 5 cycles) and RT (external beam RT - 5040 cGy in 28 fractions, followed by 4 fractions/700 cGy/weekly of brachytherapy). Eligibility criteria included histologically proven squamous cell cervical carcinoma, stage III; no prior therapy; ECOG PS <3 and adequate end-organ functions. Patients were allowed four additional weeks of toxicity observation after CRT + E before proceeding to the next cohort. Frozen tissue for molecular studies was collected before treatment. Results: Considering the first two cohorts, patients presented median age 48 (36–59), stage IIIB (all patients). Median duration of treatment was 71 (70–104) days. Most common non-hematological toxicity were mild to moderate rash, fatigue, diarrhea (grade 3 in one patient), nausea and dysuria. Grade 3 leukopenia was observed in only one patient. Dose limiting toxicities have not been reported so far. Five patients had complete response and one patient had partial response (MRI). Of note, 5/6 patients reported clinical benefit (bleeding cessation) after one week on E alone. The third study cohort (E = 150 mg) is ongoing. Conclusions: This is the first report of a combination of erlotinib, cisplatin and pelvic RT. The addition of E to standard CRT does not appear to increase in-field or systemic toxicities. MTD has not been defined so far. Final results of the phase I will be presented at the meeting. [Table: see text]
A Phase I pharmacokinetic (PK) study of single dose oral therapy with a uPA inhibitor (WX-671)
Authors: Bevan P. , Mala C. , Buergle M. , Schmalix W. A. , Neville N. G. 
Published: March 2020

13091 Background: WX-671 is an orally available prodrug of WX-UK1, a serine protease inhibitor that inhibits uPA as well as other serine proteases. WX-UK1 (Setyono-Han et al., Thromb Haemost 2005) and WX-671 have shown to efficiently reduce primary tumor growth and metastasis formation in a variety of animal models. First PK and safety data of the prodrug WX-671 were obtained in healthy volunteers. Methods: Male healthy volunteers received WX-671 as hydrogen sulfate given as single oral doses corresponding to 50, 100, 200 and 400 mg WX-671 free base. Each subject received two single doses, the first dose pre-prandially and the second dose one week later post-prandially. PK profiles were obtained over 48h for both the prodrug WX-671 and the active metabolite WX-UK1. Safety was assessed by measuring vital signs, laboratory parameters (hematology, blood chemistry, coagulation) and ECGs. Results: 16 healthy male volunteers were included, four per dose level. Both the Cmax levels as well as the plasma AUCs of both WX-671 and WX-UK1 were overproportionally related with dose levels. Administration with food slightly increased AUCs at the two higher doses. Terminal phase half life was fairly constant for WX-671 at all doses (approximately 5.8 h) and for WX-UK1 at least in the two highest dose groups with 17–21 h. Four subjects out of 16 (25%) experienced a total number of 11 adverse events. These events were nervous system disorders (headache, 7 events) and gastrointestinal disorders (diarrhea, 2 events; flatulence, 2 events). All adverse events occurred at the lower dose levels of 50 mg and 100 mg WX-671. No adverse events were observed at the dose levels of 200 and 400 mg WX-671. All adverse events were rated as mild and all subjects completely recovered within a maximum time period of 18h. Conclusions: The administration of oral doses of WX-671 (as hydrogen sulfate) resulted in the formation of WX-UK1 in the plasma uniformly across all individuals. At all dose levels tested, WX-671 was well tolerated systemically as judged by assessment of vital signs, ECG, general safety laboratory and coagulation data as well as by adverse event profiles. Two phase I PK and safety studies with daily dosing over 15 days at the above tested dose levels are currently ongoing, one in healthy volunteers and the other in patients. [Table: see text]
A phase I study of bexarotene and rosiglitazone in patients with refractory cancers
Authors: Read W. L. , Baggstrom M. Q. , Adkins D. , Suresh R. , Ghalie R. , Wildi J. , Govindan R. 
Published: March 2020

13094 Background: Preclinical studies have shown that ligands of the PPAR-γ receptor can slow growth and promote differentiation of malignant cells. Rosiglitazone is a high affinity PPAR-γ ligand approved for treatment of insulin resistant diabetes. After binding ligand, the PPAR-γ receptor heterodimerizes with the RXR receptor. Bexarotene is an RXR ligand with cytostatic properties similar to those of PPAR-γ agonists. Ligands of RXR and PPAR-γ are synergistic, causing cell differentiation and apoptosis. Methods: We conducted a phase 1 study of bexarotene and rosiglitazone in patients with resistant malignancies to define the MTD of rosiglitazone in this regimen. Patients received bexarotene 300 mg/m2 daily. The starting dose of rosiglitazone was 4 mg/day. This dose was escalated in five cohorts using the modified Fibonacchi scheme (4–6-8–10–12). Both drugs were continued until disease progression or toxicity. Patients received atorvastatin 10 mg daily, which was increased based on weekly triglyceride levels. Results: We enrolled 23 patients without encountering dose limiting toxicity. After reaching 12 mg/day of rosiglitazone, the study was closed because of laboratory evidence showing no further synergy at higher doses. Patient Characteristics: Histological type: NSCLC 8, sarcoma 3, prostate 2, and others (SCLC, thyroid/breast, mesothelioma, esophageal, breast, colorectal, renal, parotid, transitional cell, cervical). Median cycles of treatment delivered 1 (range 0–4). The primary serious adverse events (grade 3 or 4) were hyperglyceridemia (17%), dyspnea (9%), nausea (9%), dehydration (9%). Two patients expired, both due to disease progression. Responses: CR/PR none, SD 3, disease progression 14, not evaluable 4, patient withdrawal 2. Conclusions: The combination of bexarotene (300 mg/m2/day) and rosiglitazone (12 mg/day) is safe and feasible. No responses were seen in this heavily pretreated population, which is not surprising given that both agents are cytostatic, rather than cytotoxic. This combination might be studied in cutaneous T-cell lymphoma, or as adjuvant/maintenance therapy in other malignant diseases. Other areas for study might include inflammatory diseases where PPAR-γ ligands have activity. This study was supported by Ligand pharmaceuticals. [Table: see text]
Phase I trial of a histone deacetylase inhibitor (HDACI) and retinoid acid (RA) in patients (pts) with advanced solid tumor malignancies
Authors: Atieh D. M. , Milowsky M. I. , Cobham M. , Kaplan J. , Smith C. , Gudas L. J. , Nanus D. M. 
Published: March 2020

13114 Background: Transcription of RA responsive genes is inhibited by co-repressor complexes which have HDAC activity. Pre-clinical data demonstrates that addition of an HDACI to RA enhances transcription of genes that augment anti-tumor and differentiation response, and results in tumor inhibition in a RCC model (Clin Cancer Res. 2005;11:3558). Valproic Acid (VPA) has potent HDCAI activity and ATRA-IV is a liposomal RA with excellent bioavailability. The objective of this trial is to determine safety, pharmacokinetics (PK) of combination therapy, as well as correlative studies of RA receptor expression and histone acetylation status. Methods: Adults with a refractory metastatic solid tumor malignancy, KPS >60%, adequate organ function, life expectancy >3 months are eligible. 3-pt cohorts in a 2-step dose escalation: Oral VPA (Abbott Pharmaceutical) is dosed (starting at 10 mg/kg/d every 8 hrs) until trough VPA serum concentration of 50–80; 80–100 and 100–120 μg/ml. IV ATRA (Antigenics) is then administered at 60mg/m2 IV weekly. Once VPA MTD is determined, ATRA-IV is then escalated to 90, 120 and 140 mg/m2 unless DLT’s are seen. Dose levels are escalated in cohorts of 3–6 pts and cycle length is 4 weeks. Results: 9 pts have been enrolled and 5 are evaluable for toxicity of both drugs (renal cell, prostate, GE junction, bladder and small blue cell tumor). 4 pts withdrew from VPA toxicity prior to ATRA-IV. Median age 67 (range 26–79), pts received between 1–4 prior therapies (non-palliative surgery, chemotherapy, radiation, PBSCT). VPA did not alter ATRA-IV pharmacokinetics. The MTD of VPA has not yet been reached and the ATRA escalation phase has not yet been initiated. Most common toxicities observed were pain, dyspnea, gastrointestinal and neurologic. One grade 3 neurotoxic event occurred related to POD. 1 pt had a transient decline in PSA. Correlative studies are ongoing. Conclusions: Epigenetic modifications induced by HDACIs may allow the anti-tumor effects of retinoids to be realized. Toxicity of VPA has limited the addition of RA to this HDACI. HDACI + RA is a rationale approach to treat progressive RCC and future studies will incorporate more potent and less toxic HDACI + RA to treat RCC. No significant financial relationships to disclose.
Mutations of HER2 gene in HER2-positive metastatic breast cancer
Authors: Prempree T. , Wongpaksa C. 
Published: March 2020

13118 Background: HER2 status of Breast Cancer has been assessed by IHC and FISH and used for therapeutic decision with a high degree of success. However, there were numbers of HER2-positive MBC who finally failed the Trastuzumab treatment after initial good response. Mechanisms of intrinsic and acquired Trastuzumab resistance are not yet known. Our Objective is to identify factor or factors responsible for Trastuzumab resistance. Methods: DNA extraction and Sequencing of HER2 gene were performed on primary tumors of HER2-positive 14 MBC patients undergoing Trastuzumab therapy. Re-biopsy were done on new metstatic sites of those cases discovered to have Trastuzumab resistance. Results: Of 14 MBC cases whose tumors showing positive IHC and FISH, there were no mutation found in their HER2 gene, exons 18,19, 20 and 21. However, 3 of 14 cases of MBC undergoing continuous Trastuzumab therapy with excellent response for more than one year, developed the resistance. All three cases had new metstatic sites biopsied, and showed D880N and E837Y mutations in the exon 21 of their HER2 genes. All three cases showed no response to trastuzumab therapy. Conclusions: 1) HER2-positive MBC tumors did not have any HER2 gene mutations in them. 2) Mutations arised in their HER2 gene, exon 21 may be responsible for the intrinsic and acquired Trastuzumab resistance. Additional work in this area is needed to further substantiate our findings. No significant financial relationships to disclose.
Comprehensive analysis of UGT1A polymorphisms predictive for pharmacokinetics and treatment outcome in non-small cell lung cancer patients treated with irinotecan and cisplatin
Authors: Han J. , Lim H. , Lee S. , Lee D. , Kim H. , Lee J. 
Published: March 2020

13121 Purpose: To determine whether UGT1A1, UGT1A7, and UGT1A9 polymorphisms affect pharmacokinetics (PK) of irinotecan and treatment outcome of Korean patients with advanced non-small cell lung cancer (NSCLC). Methods: Eighty-one patients with advanced NSCLC were treated with irinotecan and cisplatin chemotherapy. Genomic DNA was extracted from peripheral blood and genotyped using direct sequencing. We analyzed the association of UGT1A genotypes with irinotecan PK and clinical outcomes. Results: In genotype-PK association analysis, UGT1A1*6/*6 (n = 6), UGT1A7*3/*3 (n = 6) and UGT1A9–118(dT)9/9 (n = 11) were associated with significantly lower AUCSN-38G/AUCSN-38 ratio (P = 0.002, 0.009and 0.001, respectively). In linkage disequilibrium (LD) analysis, the UGT1A7 variants were highly linked with UGT1A1*6 (D` = 0.85, r2 = 0.63) and UGT1A9*22 (D` = 0.95, r2 = 0.88), which was substantiated in haplotype analysis. Patients with UGT1A1*6/*6 had lower tumor response and higher incidence of severe neutropenia. UGT1A9–118(dT)9/9 also showed a trend for high incidence of severe diarrhea, but not tumor response. In survival analysis, patients with UGT1A1*6/*6 had significantly shorter progression-free survival (P = 0.001) and overall survival (P = 0.017). Conclusions: These findings suggest that UGT1A1*6 and UGT1A9*22 genotypes may be important for SN-38 glucuronidation and associated with irinotecan-related severe toxicity. Specifically, UGT1A1*6 might be useful for predicting tumor response and survival outcome of Korean patients with NSCLC treated with irinotecan-based chemotherapy. (Supported in part by NCC Grant 0210130 and 0510080 from National Cancer Center, Korea). No significant financial relationships to disclose.
Phase I study of ON 01910.Na by 3-day continuous infusion (CI) in patients (pts) with advanced cancer
Authors: Ohnuma T. , Cho S. Y. , Roboz J. , Jiang J. D. , Lehrer D. , Silverman L. , Schwartz J. D. , Reddy E. P. 
Published: March 2020

13137 Background: The benzyl styryl sulfone analog ON 01910.Na is a novel anticancer agent that inhibits mitotic progression and induces apoptosis; it has activity against most human cancer cells in vitro and against a broad spectrum of human xenografts in mice. Cell kill effects are exposure time-dependent in vitro. After 3d exposure 200 nM ON 01910.Na killed > 90% of Daudi lymphoma cells, whereas 40-fold higher drug concentration killed only 50% of cells after 24h exposure. Dogs that received CI of 325 mg/kg/d ×3 failed to reach MTD. Methods: Starting dose 50 mg/m2/d as a 72 hr CI was 1/10th MTD of rats’ daily dose given × 28 d. Treatment cycles were repeated every 2 wks until progressive disease, intolerable toxicity, or withdrawal of consent. Dose was escalated by Fibonacci progression in single pts until grade 2 toxicity when cohorts of 3 are to be studied. Volunteers may be retreated at a higher dose if tolerated by a preceding naïve subject. Results: One man and four women (61–77 yrs) have been studied in 21 cycles in 5 mos as of 1/10/06. Doses of 50, 100, 150 and 250 mg/m2/d × 3 have been given for 1 to 10 cycles. Grade 1 granulocytopenia (2/4 pts with carcinoma) indicates biologic activity. Grade 1 fatigue (3/5) was less than in prior chemotherapy regimens. No grade 2 toxicity has yet occurred. Cumulative toxicity has not been seen. Two pts have had stable disease 6+ and 22+ wks. After deproteinization with acetonitrile, plasma or serum samples were measured by mass spectrometry. At 100 mg/m2/d steady state levels were 730 nM after the 1st cycle and 1190 nM after the 4th cycle. Drug levels were maximal at 3 to 6 h despite CI suggesting induction of a metabolizing pathway. Levels fell precipitously at the end of infusion on the 1st cycle but a low level persisted in one pt for 48h after the major drop in the 4th cycle, suggesting drug accumulation. Conclusion: Levels effective in vitro have been obtained in vivo by CI without limiting toxicity. Hints of activity already seen suggest that this compound has clinical promise. This phase I study continues. [Table: see text]
Safety and pharmacokinetics of intravenous VEGF Trap plus irinotecan, 5-fluorouracil, and leucovorin (I-LV5FU2) in a combination phase I clinical trial of patients with advanced solid tumors
Authors: Rixe O. , Verslype C. , Méric J. B. , Tejpar S. , Bloch J. , Crabbe M. , Khayat D. , Furfine E. S. , Assadourian S. , Van Cutsem E. 
Published: March 2020

13161 Background: VEGF Trap is a potent angiogenesis inhibitor comprising portions of human VEGF receptor VEGFR1 (Flt-1) and VEGFR2 (Flk-1) extracellular domains fused to the Fc portion of human IgG. VEGF Trap binds VEGF and neutralizes all VEGF-A isoforms plus placental growth factor. I-LV5FU2 is an approved chemotherapy regimen for the first-line treatment of metastatic colorectal cancer. This study was designed to evaluate the safety and pharmacokinetics (PK) of VEGF Trap plus I-LV5FU2 administered intravenously. Methods: Successive cohorts of 3–6 patients (pts) with relapsed or refractory solid tumors received intravenous VEGF Trap plus I-LV5FU2 every 2 weeks. Study endpoints included safety, PK, and immunogenicity. Antitumor activity was assessed by CT scan. Results: Ten pts (3 male/7 female), median age 59 (34–67), ECOG PS 0/1/2: 8/2/0, with a variety of advanced solid tumors, including 5 colorectal and 2 ovarian, have received a total of 50 cycles of VEGF Trap plus I-LV5FU2 across 2 VEGF Trap dose levels (2.0 mg/kg, 4.0 mg/kg) to date. Only 1 dose-limiting toxicity (G3 proteinuria >2 wks with normal plasma creatinine levels) has been encountered so far (4.0 mg/kg, Cycle 2). This pt also had controlled G2 HTN (renal biopsy pending). No other G3/4 VEGF Trap-related AEs have been reported so far. Preliminary free VEGF Trap clearance was 15.4 mL/kg/day. Three pts (synovial sarcoma, ovarian and colon cancers) achieved partial responses. Conclusions: VEGF Trap may be safely combined with I-LV5FU2 at the dose levels studied. Preliminary free VEGF Trap clearance did not differ significantly from that seen with single-agent exposure; chemotherapy PK analysis is pending. The maximum tolerated dose has not yet been reached, and dose escalation continues. Updated safety, pharmacokinetic, and preliminary efficacy results from this ongoing study will be presented. [Table: see text]