bluuebunny/crossref_metadata_2025_split huggingface dataset:
Correlation between the EGFR intron 1 CA dinucleotide repeat and skin toxicity in lung cancer patients treated with erlotinib
Authors: Garcia-Donas J. , Leskelä S. , Sanchez J. M. , Camara J. C. , Rodriguez N. , Dhimes P. , Pinedo F. , Lopez J. L. , Jara C. , Rodriguez-Antona C. 
Published: March 2020

14001 Background: Acneiform rash is the main toxicity of erlotinib, an epidermal growth factor receptor (EGFR) inhibitor. The length of the CA dinucleotide repeat in EGFR intron 1 has been suggested to predict the biological effects of tyrosin kinase inhibitors. Thus, we compared this polymorphism with the rash severity in non-small cell lung cancer (NSCLC) patients treated with erlotinib. Methods: Toxicity was evaluated in 18 metastatic or locally advanced unresectable NSCLC patients treated orally with 150 mg/d of erlotinib: 7 retrospectively and 11 prospectively. Rash was graded according to a modified scale based on the Common Toxicity Criteria v.3.0, which subclassified grade II rash into IIA (topic intervention indicated) and IIB (oral intervention indicated). Genomic DNA was isolated from each patient; the length of the EGFR intron 1 CA dinucleotide repeat was measured by PCR amplification and analyzed on a capillary sequencer. Results: The most common EGFR genotypes were: 16, 20, 17 and 18 CA repeats (with 50, 25, 8 and 8% frequency, respectively). 33% of the subjects with a total amount of CA repeats <34 had grade IIB-III rash vs 11% of the subjects with =34 CA repeats. In addition, all patients with 0 grade toxicity belonged to the =34 CA group. When the only patient with a previous dermatological disease (psoriasis) was excluded from the analysis, the difference between both groups increased, reaching statistical significance (p=0.047). Conclusions: This data suggests that NSCLC patients with long EGFR intron 1 CA alleles present lower grades of skin toxicity when treated with erlotinib than patients with short CA alleles. Further studies are required to confirm this data. [Table: see text] No significant financial relationships to disclose.
A phase Ib study to assess the safety of lexatumumab, a human monoclonal antibody that activates TRAIL-R2, in combination with gemcitabine, pemetrexed, doxorubicin or FOLFIRI
Authors: Sikic B. I. , Wakelee H. A. , von Mehren M. , Lewis N. , Calvert A. H. , Plummer E. R. , Fox N. L. , Howard T. , Jones S. F. , Burris H. A. 
Published: March 2020

14006 Background: Lexatumumab (HGS-ETR2) is a fully-human agonistic monoclonal antibody that targets and activates the Tumor Necrosis Factor-Related Apoptosis-Inducing Ligand Receptor 2 (TRAIL-R2). TRAIL-R2 is a member of the Tumor Necrosis Factor Receptor (TNFR) superfamily that, when activated, induces apoptosis via the extrinsic pathway. Lexatumumab shows promising anti-tumor activity in preclinical models, particularly in combination with chemotherapeutic agents. Single-agent lexatumumab was well-tolerated in phase I trials. This is the first study of the safety of a TRAIL-R2 agonist in combination with chemotherapy. Methods: Patients for whom gemcitabine, pemetrexed, doxorubicin or FOLFIRI was considered an appropriate treatment received one of the full-dose chemotherapy regimens plus lexatumumab every 2 weeks (for gemcitabine and FOLFIRI) or 3 weeks (for pemetrexed and doxorubicin). Four to 6 patients were treated with 5 mg/kg lexatumumab in each chemotherapy cohort prior to dose escalation to 10 mg/kg. Results: To date, 41 patients with a wide range of cancer types have received 164 courses of lexatumumab over the 2 dose levels. The majority (33/41) received at least 2 courses (range 1 to 19). Lexatumumab was well-tolerated; no dose reductions of lexatumumab were required. Severe adverse events considered at least possibly related to lexatumumab included anemia, fatigue and dehydration. Tumor shrinkage has been observed, including confirmed partial responses (PRs) in the FOLFIRI and doxorubicin arms. Eight patients continue on study. Conclusions: Lexatumumab can be safely administered in combination with a wide range of chemotherapeutic agents. Evaluation of the efficacy of lexatumumab in combination with chemotherapy in Phase 2 trials is warranted. [Table: see text]
A phase I and pharmacokinetic/pharmacodynamic study of vorinostat (suberoylanilide hydroxamic acid, SAHA) in Japanese patients with solid tumor
Authors: Fujiwara Y. , Yamamoto N. , Yamada K. , Yamada Y. , Shimoyama T. , Koizmi F. , Nishio K. , Otsuki T. , Frankel S. R. , Tamura T. 
Published: March 2020

14015 Background: Vorinostat (Zolinza™), a potent inhibitor of histone deacetylase (HDAC), induces tumor growth inhibition, differentiation, and apoptosis in vitro. Increasing evidence has revealed clinical activity of vorinostat in patients (pts) with various types of cancer including cutaneous T-cell lymphoma. Methods: Japanese pts with solid tumor who failed standard therapy were enrolled in a single institution, National Cancer Center hospital, Phase I study. Pts were dosed with vorinostat BID for 14 consecutive days followed by 7 day-rest starting at 100 mg and escalated by 100 mg BID until MTD was established. Subsequently single daily dosing was tested at 400 and 500 mg. PK was measured at total of 41 timepoints. Response was also evaluated according to the international workshop criteria. Results: MTD was established as 200 mg BID and 500 mg QD for 14 consecutive days followed by a 7 day-rest. All 18 enrolled pts were assessed for safety and PK. Median age was 58 yrs [25–72]. Ten of 18 pts had lung cancer. Two of 6 pts receiving 200 mg BID experienced DLTs: Grade 4 thrombocytopenia, and Grade 4 thrombocytopenia and Grade 3 anorexia. None of 3 pts receiving 400 mg QD experienced DLT. One of 6 pts receiving 500 mg QD experienced Grade 3 anorexia and fatigue. AUC of vorinostat increased generally proportional to dose in the range of 100–500 mg. PK was not greatly affected by multiple doses. Intact drug was hardly excreted in urine (<1% of dose). PK profile is similar to that established in US pts. As of Dec 2006, 1 pt with invasive thymoma received 200 mg BID for 1 yr. Nine pts achieved SD as best response. Conclusions: This study demonstrates the safety of vorinostat 200 mg BID and 500 mg QD for 14 consecutive days followed by 7 day-rest. These would be the RD for Phase II studies on this schedule. No significant financial relationships to disclose.
A phase I study of BMS-582664 (brivanib alaninate), an oral dual inhibitor of VEGFR and FGFR tyrosine kinases, in combination with full-dose cetuximab in patients (pts) with advanced gastrointestinal malignancies (AGM) who failed prior therapy
Authors: Garrett C. R. , Siu L. L. , Giaccone G. , El-Khoueiry A. , Marshall J. , LoRusso P. , Velasquez L. , Kollia G. , He P. , Feltquate D. 
Published: March 2020

14018 Background: Brivanib is an oral prodrug of BMS-540215, a dual tyrosine kinase inhibitor of VEGFR and FGFR signaling. Prior studies have validated both VEGF and EGF signaling pathways as targets in AGM. The MTD of single-agent brivanib is 800 mg qd (ASCO #3051, 2006). Methods: An open-label Phase I dose-escalation study of brivanib in combination with cetuximab was conducted in pts with AGM who failed prior therapy. Brivanib was given po Day 1 and qd from Day 8, starting at 320 mg. Cetuximab was given IV Day 8 (400 mg/m2) then weekly (250 mg/m2). Dose escalation of brivanib continued to 800 mg qd, when an expansion cohort for pts with colorectal cancer (CRC) was opened for additional safety and efficacy. Fresh tissue and blood sampling for biomarker and pharmacokinetic (PK) analysis was performed. FDG-PET was obtained at Baseline X 2, Days 15 and 56. Tumor response (modified WHO) was evaluated q 8 weeks. Results: 18 pts (15 CRC, 2 esophageal, 1 other) were treated with 320, 600 or 800 mg qd of brivanib in combination with cetuximab for a median of 8 weeks (range 1 - 20+). A single DLT, bilateral pulmonary emboli, occurred at 320 mg qd. Few treatment-related AEs occurred across the 3 cohorts (Table). PK/biomarker data is pending. Available FDG-PET results from measurements in 8 pts with 2–3 target lesions showed good baseline reproducibility in SUVpeak, SUVmean and SUVmax, with intra-subject CV of 3.6%, 7.2% and 9.3%, respectively. Conclusions: Brivanib in combination with full-dose cetuximab was well tolerated at ≤800 mg qd and did not result in enhancement of cetuximab associated AEs. Pre-treatment FDG-PET is a highly reproducible imaging modality. [Table: see text] [Table: see text]
Clinical response to targeted radionuclide therapy with multiple 500 mCi doses of 111In-pentetreotide in patients with progressive neuroendocrine tumors
Authors: Delpassand E. S. , Sims-Mourtada J. , Azhdarinia A. , Ashoori F. , Sureshbabu W. , Hernandez J. , Torabi F. , Espenan G. , Woltering E. A. , Anthony L. B. 
Published: March 2020

14027 Background: Patients with advanced stage neuroendocrine tumors have limited therapeutic options. Previous treatments with doses up to 360 mCi per fraction have shown promising results in stabilizing progressive disease. The intent of this study was to evaluate the efficacy and safety of 2 consecutive 500 mCi doses of 111In-pentetreotide in patients with progressive neuroendocrine tumors. This study was performed according to an FDA approved IND application. Methods: In a non-randomized study, 18 patients (13 men, 5 women) with an average age of 59 (ranging from 41–83 yr.) received 2 cycles of 500 mCi 111In-pentetreotide infused over 3 to 6 hours (avg. cumulative dose range: 955–1006.1 mCi). All patients had progressive neuroendocrine tumors and failed first line therapy. All patients had grade 3 to 5 uptake in the tumors in the pre-therapy diagnostic 111In-pentetreotide scan. The primary endpoint was clinical, metabolic and imaging response using RECIST criteria. Early and long term hematological, renal and hepatic toxicities during the average follow up period of 9.87 months (range 3.93 to 17.23 months) was performed using NCI Common Toxicities criteria. Results: Sixteen out of 18 patients with previously progressive disseminated neuroendocrine disease achieved stable disease by imaging criteria. Metabolic response defined as 25% or more decline in Chromogranin or other markers was achieved in 72% of the patients. Clinical response defined by Functional Living Index (FLI) questionnaire and physical exam was achieved in 84% of the patients. Ten patients (55%) had grade I or II hematological toxicities, one patient had grade III thrombocytopenia, with nadir mean of 5 weeks after therapy. None of the patients required supportive therapy. Duration of hematological toxicities ranged from 1–6 weeks). One patient had grade II liver toxicity which appeared 4 weeks after therapy and resolved on week 5. No renal toxicity was observed during the follow-up period. Conclusions: Multiple 500 mCi doses of 111In-pentetreotide therapy are effective in patients with progressive disseminated neuroendocrine tumors. Safety profile of this regimen suggests the opportunity for non-myeloablative dose escalation. No significant financial relationships to disclose.
A phase I dose-escalation study of the safety and pharmacokinetics (PK) of XL184, a VEGFR and MET kinase inhibitor, administered orally to patients (pts) with advanced malignancies
Authors: Salgia R. , Hong D. S. , Camacho L. H. , Ng C. S. , Janisch L. , Ratain M. J. , Kurzrock R. 
Published: March 2020

14031 Background: XL184 is a potent orally available small molecule inhibitor of MET and VEGFR2/KDR, and also inhibits KIT, RET, FLT3, and Tie-2. Methods: This is a ph 1 cohort dose escalation study. Pts with advanced malignancies are treated with 2 cycles of XL184 orally daily for 5 consecutive days every 2 weeks. Response is assessed every 8 wks by RECIST criteria and pts with SD or better receive maintenance therapy. Plasma markers of angiogenesis VEGF-A, sVEGFR2 and Ang2 are being analyzed. Results: A total of 25 pts with advanced malignancies have been treated across 7 dose levels: 0.08 to 5.12 mg/kg. A total of 10 pts have had SD lasting > 3 months. Three pts with medullary thyroid carcinoma (one of whom had a documented RET mutation) had substantial reductions in plasma calcitonin. Three pts have had stable disease for over 6 months, including 1 pt with carcinoid (20% decrease in liver metastases) and 1 pt with T- cell lymphoma (on treatment for >12 mos). One pt with papillary renal cell cancer, a disease that sometimes bears activating MET mutations, demonstrated 9% tumor reduction at first restaging. There have been no DLTs to date. Preliminary PK analysis (0.08–1.28 mg/kg) suggests linear PK with average Cmax values 34.2, 70, 198, 322 and 603 ng/mL following the fifth dose at 0.08, 0.16, 0.32, 0.64 and 1.28 mg/kg, respectively. The terminal half-life is 80–90 hrs, resulting in concentrations exceeding 200 ng/mL for 96 hours following the fifth dose at 1.28 mg/kg. Conclusions: XL184 appears generally well tolerated at doses tested to date. XL184 has a long terminal half-life. Early signs of antitumor activity have been observed, at doses not associated with toxicity, in patients with various cancers, including but not limited to those that may have RET (medullary thyroid) or MET (papillary renal) mutations. No significant financial relationships to disclose.
Clinical evaluation of nitric oxide responses to anti-VEGF therapy with bevacizumab
Authors: Nixon A. , Allen J. , Miller E. , Savage S. , Kaplan N. , Starr M. , Bendell J. , Uronis H. , Fernando N. , Hurwitz H. 
Published: March 2020

14039 Background: Anti-vascular endothelial growth factor (anti-VEGF) therapy has been linked to hypertension (HTN) and arterial thrombo-embolic events that may involve changes in nitric oxide (NO) bioavailability. Methods: 25 patients (pts) with advanced cancer, normal renal function and blood pressure (BP), no increased risks for anti-VEGF toxicities, and not on medications known to confound biomarker studies (including anti-hypertensives) were treated with bevacizumab (BV) 15mg/kg d1, then 10mg/kg q2 week. Prior to biomarker assessment, all patients were placed on a calorie-, nitrate-, and salt-restricted diet for 72 hr. All measures were taken pre-treatment (preRx) and on day 28 of treatment (onRx). Dependant variables included; a) Brachial artery reactivity (BAR) following hyperemic flow stimulus (endothelium-dependent) and sub-lingual nitroglycerine (NTG; endothelium-independent); b) exhaled and plasma/urine total NO2/NO3 using chemiluminescence (Sievers 280NOA) with either KI or VCl3 in HCl as the reductants; c) blood pressure. Additionally, we measured multiple regulators of vascular tone and injury. Comparisons were analyzed using Spearman signed rank tests. Results: Of 25 pts (16 F, 9 M) treated, 21 patients were fully evaluable. Significant changes or strong trends were observed upon comparing preRx vs. onRx for BP (SBP +12.4, DBP +5.6, MAP +7.9 mm Hg), and flow-mediated BAR (-2.0%) with no changes in hyperemic flow/shear stimulus or smooth muscle function (BAR NTG), indicating a decrease in brachial artery endothelial responsiveness. Exhaled NO decreased (-0.8% d1vs d28 and -0.6% pre/post infusion day1). Measurement and data analysis of urinary/plasma NO2/NO3, as well as angiogenic markers, are almost complete and will be reported. Conclusions: After one month of treatment, BV increased BP and decreased endothelium- dependent BAR and exhaled NO, suggesting potentially broad, mechanism-based effects on NO bioavailability in patients. [Table: see text]
Effectiveness of the dual specific Src/Abl kinase inhibitor AZD0530 in combination with tamoxifen in preventing acquired anti-estrogen resistance in breast cancer cells
Authors: Hiscox S. , Green T. P. , Smith C. , Jordan N. , James M. , Nicholson R. 
Published: March 2020

14054 Background: AZD0530 is a novel, orally potent, once-daily, highly selective and dual-specific Src/Abl kinase inhibitor with potential for activity in a wide range of tumors. In the context of breast cancer, where tamoxifen resistance presents a major problem, Src inhibition may be a particularly valuable therapeutic strategy since we have previously observed that elevated Src kinase activity accompanies anti-estrogen resistance in vitro, promoting an aggressive cell phenotype. Here, we have explored the potential therapeutic effects of Src inhibition with AZD0530, alone and in combination with tamoxifen, on the acquisition of endocrine resistance in breast cancer cells. Methods: MCF7 and T47D breast cancer cells were exposed to tamoxifen (10–7 M), AZD0530 (1 μM), or both agents in combination for a minimum of 10 months with passaging as necessary, or until total cell death occurred. Cells were assayed at monthly intervals for intracellular signaling pathway activity (Western Blotting) and in vitro invasive capacity (Matrigel invasion assays). Apoptosis and proliferation were assessed by ELISA and Ki67 staining, respectively. Changes in c-Myc and cyclin-D1 were measured with RT-PCR. Results: Treatment of cells with tamoxifen alone ultimately resulted in acquired resistance, elevated Src kinase activity, and a Src- dependent increase in invasive capacity. Chronic exposure to AZD0530 alone resulted in outgrowth of AZD0530 resistant cells, in which Src kinase activity remained suppressed as did their in vitro invasiveness. Treatment of MCF7 and T47D cells with AZD0530 and tamoxifen combined resulted in a reduction of Src, FAK, and Akt activity, inhibition of c-Myc gene expression, and complete abrogation of their in vitro invasive behavior. Furthermore, combination treatment completely prevented cell proliferation and the subsequent emergence of a resistant phenotype, with a total loss of cells by 12 weeks. Conclusions: Inhibition of Src kinase with AZD0530, when used in conjunction with anti-estrogen therapies, effectively prevents acquired resistance in breast cancer cells in vitro suggesting a potential novel therapeutic benefit of Src kinase inhibitors clinically. No significant financial relationships to disclose.
Effect of sorafenib in symptomatic metastatic medullary thyroid cancer
Authors: Kober F. , Hermann M. , Handler A. , Krotla G. 
Published: March 2020

14065 Background: RET receptor tyrosin kinase activity plays a major role in medullary thyroid cancer (MTC) tumor growth. Sorafenib is an oral agent that selectively targets RET tyrosine kinases. Methods: 5 patients (pts) with metastatic MTC with excessive elevation of calcitonin(CTN) serum levels entered this pilotstudy. Hypercalcitonemia-related symptoms were present in all pts (3 severe diarrhea, 2 moderate) and metastasis- related symptoms were present in 4 pts (2 severe pain, 2 moderate). All pts had had prior thyreoidectomy and cervical +- mediastinal lymphnode dissection, 4 pts had prior octreotide therapy, 3 prior chemotherapy. Pts received 800 mg or 400 mg (weight < 50 kg) Sorafenib as a starting dose. According to the protocol, the dose was reduced gradually in 200 mg scale when pts revealed therapy induced side effects to avoid worsening of quality of life. Sorafenib has to be administered at least 3 months, the scheduled duration of therapy was 6 months. Physical examination, calcitonin and CEA levels were monitored every 4 weeks, measurable metastatic lesions were controlled by appropriate means 3 and 6 months after starting therapy. Primary objective was to assess the effect on CTN dependent symptoms, second objectives included assessments of tumor response (RECIST) and biochemical response. Results: After 2–3 months CTN decreased to levels >50% of baseline in all pts, to levels >90% in 2 pts. According to that all pts were free of CTN related symptoms after 4 weeks. In 4 pts CEA levels reacted in a similar way. After 6 months controls of metastatic lesions were classified as CR-1 pt, PR-1 pt, NC-3 pts. 2 pts with severe metastasis-related pain were off analgesics after 3 months of treatment. Due to side effects Sorafenib dosage was reduced to 50% of the initial dose in all patients. Interestingly marked TSH - elevations were observed in 3 pts which indicates a direct influence to the hypothalamic-pituary-axis. Conclusion: Sorafenib has to be considered as an effective teatment of symptomatic, metastatic MTC. No significant financial relationships to disclose.
A phase I trial of RAD001 in combination with cetuximab in patients with advanced solid tumors
Authors: Avadhani A. N. , Flaherty K. , Rosen M. , Veronese M. L. , Harlacker K. , Johnson S. W. , Sherman E. , Griggs W. , Divgi C. R. , O’Dwyer P. J. 
Published: March 2020

14075 Background: Cetuximab is a selective epidermal growth factor (EGFR) inhibitor approved for use in EGFR expressing advanced colorectal cancers. RAD001 inhibits mTOR (mammalian target of rapamycin), a downstream effector of the PI3K/AKT pathway. Preclinical studies suggest that RAD001 may restore sensitivity to EGFR inhibitors in resistant cell lines, and that in combination it may augment anti-tumor activity. We assessed safety, pharmacokinetics (PK), and pharmacodynamic (PD) endpoints for mTOR inhibition and tumor vascular permeability in a phase I combination study. Methods: Pts with EGFR-expressing advanced solid tumors were randomized to a 3 week run-in of single agent RAD001 or cetuximab Q wk, followed by RAD001 + cetuximab Qwk. RAD001 was dosed at 30–70 mg PO. Standard dosing of cetuximab was used (400 mg/m2 IV loading, followed by 250 mg/m2 IV Qwk). DLT was defined as any grade 4 hematologic or =grade 3 non-hematologic toxicity associated with treatment during cycle 1. In addition to plasma analysis for the PK of RAD001, we performed 18FDG-PET and dynamic contrast-enhanced (DCE) MRI before and during combination therapy, to assess for early changes in tumor metabolic activity and vascular permeability. Phosphorylation of p70S6K, a biomarker for RAD001 activity, was measured in peripheral blood mononuclear cells. Results: 12 pts (median age 56, 5 M/7F, median PS 0) were treated at dose levels 1–2 (RAD001 30–50mg/cetuximab 250 mg/m2), with 3 per dose order. Observed toxicities were all grade 1–2, and included mucositis (2/12), rash (8/12), fatigue (6/12), anorexia (4/12), nausea (5/12), and vomiting (5/12). 2 pts (parotid and ovarian CA) had SD (4+ mos) as best response, with decreased serum CA-125 in the ovarian CA pt. PET findings in pts with SD confirm decreased tumor metabolic activity. Conclusions: At these doses, neither drug appears to increase the toxicity of the other. Analysis of full dose RAD001 in the combination is nearing completion. Preliminary PET findings suggest biological activity of the combination. No significant financial relationships to disclose.