bluuebunny/crossref_metadata_2025_split huggingface dataset:
A phase I study of intravenous (IV) milataxel in combination with carboplatin in adult patients with advanced malignant solid tumors
Authors: Flood W. A. , Lewis L. D. 
Published: August 2020

e13525 Background: Milataxel (MXL) is a novel taxane with activity in human xenograft models against tumors resistant to paclitaxel. The primary objective of this study was to determine the MTD when MXL was given intravenously in combination with a fixed dose (AUC=6) of carboplatin (C) every 21 days in subjects with advanced malignant solid tumors. Secondary objectives were to (i) assess the safety and tolerability of the combination (ii) define the pharmacokinetics of MXL and C when given in combination (iii) obtain preliminary information on the antitumor activity of MXL+C. Methods: Key subject eligibility criteria included: adult pts with refractory malignant tumors, ECOG PS <3 and adequate hematologic, hepatic and renal function. PK data was obtained on day 1 for MXL and both free and bound platinum. Results: 11 pts (median age 60; 2 F,9 M) were treated. MXL was dose escalated in three cohorts (15, 20 and 25 mg/m2). Three patients were treated at 15 mg/m2 of MXL without a DLT. At the 25 mg/m2 dose of MXL there were two DLT's out of the 4 pts enrolled at this dose (1 pt - grade 3 febrile neutropenia, grade 4 thrombocytopenia; 1 pt - grade 4 ANC, grade 4 thrombocytopenia). At the 20 mg/m2 dose of MXL there were two DLT's out of the 4 pts enrolled at this dose with both pts having grade 4 ANC. The MTD and the recommended Phase II dose of MXL was 15 mg/m2 plus C (AUC= 6). The median number of cycles administered was 3 (range 1–16). The most frequent grade 3 or 4 treatment emergent adverse events were neutropenia (82%), leukopenia (55%), pancytopenia (27%), asthenia (18%), generalized edema (18%), thrombocytopenia (18%), anemia (18%), confusion (18%), and dyspnea (18%). One pt in the MTD cohort with cholangiocarcinoma had a PR. This patient received 16 cycles of therapy and had a response duration of 378 days and a TTP of 406 days. PK data (n=9) showed the elimination half-life of MXL ranged from 26 to 110 h, and that for free and total platinum were as would be predicted for C monotherapy. Conclusions: The MTD of MXL was 15 mg/m2 IV per three week cycle when combined with carboplatin (AUC= 6). One patient with a cholangiocarcinoma had a sustained PR for 378 days. No significant financial relationships to disclose.
Electrochemoterapy (ECT) for the treatment of superficial tumor localizations
Authors: Guida M. , Porcelli G. , Ruggieri E. , Zito A. , Mattioli V. , Montemurro S. , Colucci G. 
Published: August 2020

e13526 Background: ECT is an effective local treatment for palliation on inoperable superficial neoplastic lesions from any type of tumour. It combines chemotherapy and electric pulses that permeabilize the cell membrane in a transient and reversible manner, allowing low-perrneant drugs to enter the cell, thus magnifying their cytotoxicity. Recent1y, a new device (Clinoporetor, IGEA-Srl, Italy) has been developed to supply electric pulses with appropriate parameters permitting the clinical use of ECT. Methods: We treated 26 pts, M/F 12/14; median age 61 yrs, range 38–87: 7 breast cancer with nodular or infiltrating lesions in thoracic or abdominal wall; 12 melanoma (2 wide infiltration of thoracic wall, 10 in transit metastases or loco-regional recurrences); 2 head-neck cancer with a wide neck-scalp infiltration; 3 lymphomas with cutaneous lesions, 1 soft tissue sarcoma with a subcutaneous recurrence, 1 gastric cancer with 2 cutaneous localizations. The areas treated ranged from 1 to 30 cm on diameter. 12 pts requested a prior surgery debulking and 3 pts received ECT in pre-irradiated area. Intravenous bleomycin (15 mg/m2) were used in all patient; electric pulses were than applied to the tumor areas by needle electrodes in a time window of 20 minutes. In total 32 procedures were performed, 6 as out-patient in local anaesthesia and 26 in general anaesthesia; 6 pts requested a second application. Results: Treatment was safe and well tolerated, particularly when general anaesthesia was used. At the second/third week, all pts showed a regression of almost all lesions with a necrotic, fibro-sclerotic evolution. After 1–2 months from ECT, we obtained a 70% CR and a 10%PR of the lesions. Some pts showed a response after the second procedure. About 50% of lesions remained in remission for a long period (median 8 months, range 1–23+); 11 of 12 pts previously undergone surgical debulking never relapsed in the treated area. Concomitant systemic treatment, no rapid spreading of the disease and surgical debulking were related to a better local control and survival. Conclusions: ECT is a promising and safe treatment for superficial lesions from different malignancies. General anaesthesia and surgical debulking permit to treat very large and deeper lesion with a very good local control. No significant financial relationships to disclose.
Expression of breast cancer resistance protein (BCRP) in esophageal cancers (EC)
Authors: Bharthuar A. , Khoury T. , Haas K. N. , Mashtare T. , Black J. , Baer M. , Yang G. , Khushalani N. , Iyer R. V. 
Published: August 2020

e13529 Background: EC patients face a dismal outcome despite tri-modality management strategy. Median survival remains 15–18 months despite platinum, fluropyrimidine & irinotecan based therapy. BCRP is an ATP-dependent efflux protein associated with chemotherapy (CT) (e.g. irinotecan) resistance. Role of BCRP expression in EC and normal esophageal cells is not known. We examined the expression of this protein and correlate it with survival (OS) in patients receiving irinotecan-based CT. Methods: With IRB approval, 40 cases of EC diagnosed between 2004 and 2008 were stained for BCRP expression by IHC & scored by the pathologist blinded to clinical data. Baseline demographics, therapy given & OS data were collected and correlated with BCRP expression. BCRP score (membrane or cytoplasm) >/= 30 was considered positive (calculated by multiplying BCRP intensity and % staining). Fisher's exact test used to determine association between BCRP expression & demographics. Cox proportional hazards model used for association of BCRP & OS. Results: Baseline patient and tumor characteristics: Gender: M 35, F 5; Histology: 37 Adenoca & 3 SCC; Stage 1-III 27, Stage IV 10, unknown 3; CT: cisplatin+irinotecan (n=16), oxaliplatin+fluoropyrimidine (n=8), other (n=16); IHC: 30 of 40 cancers (75%) expressed BCRP [strong (n=28) & intermediate (n=3); membranous (n=17), cytoplasmic (n=27) & both (n=14)]. Down-regulation of BCRP expression in tumor compared to normal cells seen in 40% of patients. Median OS was 19 months with no difference in OS between BCRP positive and negative patients (p=0.13). Estimated hazard ratio (HR) of death for BCRP positive patients was 2.29 (95% CI 0.79 - 6.64).There was no association between BCRP expression and stage, age, gender or histology. For patients who received cisplatin and irinotecan as first line CT there was no difference in OS (p=0.39) of BCRP negative versus positive patients. Conclusions: BCRP expression is seen in a majority of EC & normal esophageal mucosa. Response rates to irinotecan based therapies are seen in 30–40 % of EC, whether the 40% with low tumor BCRP constitute a majority of the responders needs to be prospectively validated in a larger dataset & should include markers that predict response to 5-FU & platinum based CT to allow individualizing therapy for this cancer. No significant financial relationships to disclose.
A phase I evaluation of intravenous (IV) 131I-chlorotoxin delivery to solid peripheral and intracranial tumors
Authors: Gribbin T. E. , Senzer N. , Raizer J. J. , Shen S. , Nabors L. B. , Wiranowska M. , Fiveash J. B. 
Published: August 2020

e14507 Background: Pre-clinical studies demonstrate TM601 binding to glioblastoma, melanoma, and other tumor types in vitro and in vivo (human xenograft tumors in mice). Here we report imaging and safety data from a Phase I clinical trial in patients with recurrent metastatic somatic and/or cerebral solid tumors that received IV 131I-TM601. Methods: Patients received an IV imaging test dose of 10 mCi/0.2mg 131I-TM601. Subjects not showing tumor localization, received a second imaging test dose of 20 mC/0.4mg 131I-TM601. Subjects without localization at either dose were dropped from study; patients showing tumor localization without toxicity then received a 30 mCi/0.6mg 131I-TM601 IV injection. The primary objectives were to: 1) determine whole body localization and dosimetry, 2) estimate the maximum tolerated dose based on normal tissue dosimetry and 3) determine the acute toxicity of IV 131I-TM601. Results: A total of 44 evaluable patients received IV doses of 131I-TM601 without dose-limiting toxicity. 31/44 (70%) showed tumor specific uptake on follow-up gamma camera or SPECT imaging. Tumor-specific uptake was observed in patients with malignant glioma (7/8), metastatic melanoma (7/7), non-small cell lung cancer (3/4), colon cancer (6/7), pancreatic cancer (2/3), prostate cancer (2/2), breast cancer (1/4) and in one evaluable patient each with transitional cell carcinoma, pleomorphic xanthoastrocytoma and metastatic paraganglioma. Notably, all patients with metastatic cerebral disease showed tumor-specific uptake of systemically injected 131I-TM601. No uptake was seen in CNS lymphoma (n=1), ovarian (n=2), small cell lung (n=2), or medulllary thyroid cancers (n=1). Conclusions: Tumor-specific uptake of IV 131I-TM601 in primary and metastatic (including brain) solid tumors suggests that further dose escalation is warranted. Notably, IV injected 131I-TM601 crossed the blood brain barrier. Based on normal tissue dosimetry from this study, future clinical trials will evaluate safety and therapeutic efficacy in patients with recurrent glioma and metastatic melanoma at doses up to 100 mCi 131I-TM601 (maximum single dose). [Table: see text]
A novel mutant-enriched liquidchip for detection of circulating EGFR mutations in advanced non-small cell lung cancer patients
Authors: Lu S. , Yang H. , Ye X. , Xu X. , Li Z. , Ren L. , Xu Y. , Xu J. 
Published: August 2020

e14526 Background: We developed a novel technology, Mutant-enriched liquidchip (MEL), which integrates the sensitive mutant enriched PCR and quantitative high throughput liquidchip (suspension array), to detect circulating EGFR mutations (Exon 19 deletion and exon 21 L858R mutation) in patients with advanced non-small cell lung cancer (NSCLC). Methods: To enrich mutant EGFR, a unique restriction site is introduced into the mutation alleles so that the wild type sequence can be selectively removed by restriction digestion, and the undigested mutated DNA is amplified by PCR. The product is then hybridized to complementary probes (including 15 types of exon 19 deletion and exon 21 L858R mutation) which had been conjugated to beads coding with different fluorescent dye, followed by measuring through Luminex 200 system. Plasmid DNA mixture with different EGFR genotypes was applied to determine the sensitivity and accuracy of MEL. Afterwards, the MEL was validated in 49 patients whose EGFR genotypes of tissue specimen had been tested with direct sequencing The circulating genomic DNA was obtained from serum sample of other 201 Chinese stage IIIB or IV NSCLC patients without EGFR-TKI administration, and the EGFR mutation status was analyzed by using of MEL. Results: The results shows that MEL is capable of detecting as few as 20 copies of mutant EGFR alleles with a sensitivity limit of at least mutant/wild-type ratio of 0.1%. It also shows that MEL can not only confirm EGFR mutations status in tissue specimens already known by direct sequencing (13/49), but also detect mutations in some of those showing wild type by sequencing (16/49). Overall, 54% of patients had circulating EGFR mutation. 34% of patients had an exon 19 deletion and 29.6% had L858R. 63.1% of mutations were found in females and 67.6% in never-smokers. Conclusions: This novel MEL method allows for highly sensitive and reproducible detection of human somatic mutations in heterogeneous specimens, and could be applicable to test EGFR mutations non-invasively in advanced NSCLC patients for predicting response to targeted therapy. No significant financial relationships to disclose.
A phase I dose-escalation study of 5-day intermittent oral lapatinib therapy with biomarker analysis in patients with HER-2–overexpressing breast cancer
Authors: Chien A. J. , Auerback G. , Rugo H. S. , Melisko M. , Munster P. N. , Khanafshar E. , Ordovas K. G. , Petricoin E. F. , Koch K. M. , Moasser M. M. 
Published: August 2020

e14530 Background: Although current HER2 targeting agents have made measurable impact on the treatment of HER2overexpressing breast cancer, their effects have been modest. Recent evidence has redefined the target of interest as the HER2-HER3 signaling dimer and identified inherent signal buffering capacity that protects it against partial inhibitors of HER2 function. In preclinical studies, HER2 catalytic function and HER2-HER3 signaling can be suppressed, but this requires higher fully inactivating doses of HER- family tyrosine kinase inhibitors (TKIs) leading to apoptotic tumor cell death. We hypothesize that TKIs may be much more clinically effective if used at much higher and fully inactivating doses. Such high dosing may only be tolerable if given intermittently rather than continuously. Methods: To test this hypothesis clinically, we conducted a phase 1 dose-escalation study of a 5-day course of lapatinib (Lp) in women with advanced HER2-overexpressing breast cancer. Lp was administered on days 1–5 of a 14 day cycle. Starting Lp dose was 1750 mg/day and was escalated in cohorts of 3 until the maximum tolerated dose (MTD) was defined. The first cycle of Lp therapy was bracketed by tumor fine needle aspirations and serologic studies, performed at baseline and on day 5. Functional signaling pathway biomarker analysis was performed on tumor lysates using Reverse Phase Protein Microarrays to assay the inactivation of HER2-HER3 signaling. Plasma Lp concentration was assayed at all dose levels and cardiac function was rigorously monitored. Tumor core biopsies were performed on a subset of patients at the MTD to determine tissue Lp levels. Results: 17 patients have been treated to date. No grade 4 or serious adverse events (AEs) attributable to Lp have been noted. 1 patient experienced dose-limiting toxicity at dose level 6 (7000 mg/day) consisting of grade 3 diarrhea despite maximal anti-diarrheal support. There have been no cardiac AEs. The most common AEs include grade 2 diarrhea, nausea, vomiting, acne. Conclusions: The MTD and systemic exposure of Lp can be considerably increased throsugh intermittent dosing. [Table: see text]
Pharmacogenomic analysis of the triplet combination of gemcitabine, oxaliplatin, and cetuximab as salvage therapy for metastatic colorectal cancer (mCRC) patients
Authors: Hernandez A. , Bandres E. , Rodriguez J. , Bitarte N. , Ramirez N. , Zarate R. , Abajo A. , Chopitea A. , Viudez A. , Garcia-Foncillas J. 
Published: August 2020

e14531 Background: We have previously reported that biweekly gemcitabine-based therapy was active in pretreated mCRC pts (De la Cruz et al, ASCO GI 2008, abstr 377). We aimed to investigate whether germ line polymorphisms may be predictors of clinical outcome in mCRC pts treated with this combination. Methods: We evaluated SNPs of genes involved in gemcitabine metabolism (CDA, dCDK, RRM1, DCTD, SLC28A1), DNA repair (XRCC1, XRCC 3, ERCC1, XPD) and two IgG Fcγ R polymorphisms (Fcγ RIIa- H131R and Fcγ RIIIa-V158F), reported to be predictive of cetuximab-based therapy, even in K-ras mutated pts. Whole blood was collected and DNA extracted from peripheral lymphocytes using a DNA isolation Kit (Qiagen, CA). Polymorphisms were detected using the TaqMan genotyping assays (Applied Biosystems, CA). Clinical response was evaluated according to RECIST criteria. Univariate analysis (Fisher´s exact test for response; log-rank test for TTP and OS) was performed to examine associations between polymorphisms and clinical outcome. Results: Blood samples of 35 out of 39 enrolled pts were tested for genomic analysis. Patient‘s characteristics are as follows; M/F: 26/13, median age: 59 years, median number of prior chemotherapy lines: 2 (1–4), Köhne risk groups; low: 8 pts, intermediate: 18 pts, high: 13 pts. After a median follow-up of 20 months, median progression-free survival (PFS) is 6.7 months (95% CI; 5.2–8.3) and median overall survival 15.4 m (95% CI; 14.7–16.1). Overall response rate (ORR) was 53.8%. RRM1 R284R SNPs (p=0.06), T741T (p=0.02) and RRM1–524CT (p=0.04) were linked to clinical responsiveness. All pts possessing 2 or 3 favourable RRM1 SNPs responded. ORR was 53.3% for pts with no favourable SNPs versus 85% for pts with any favourable SNP (p=0.04). ORR was also significantly higher in pts with any histidine allele in the Fcγ RIIa polymorphism (93% vs. 60%, p=0.034). Median PFS was adversely affected in pts harbouring no favourable RRM1 SNPs (4.2m versus 6.7 months, p=0.019) and in those pts with homozygous Fcγ RIIa-131R allele (4.4 vs. 7.5 months, p=0.007). Conclusions: Polymorphic variants of RRM1 and Fcγ RIIa may play a key role in the efficacy of gemcitabine and cetuximab-based therapy for mCRC pts. No significant financial relationships to disclose.
A phase I study of daily BIBW 2992, an irreversible EGFR/HER-2 dual kinase inhibitor, in combination with weekly paclitaxel
Authors: Ang J. , Mikropoulos C. , Stavridi F. , Rudman S. , Uttenreuther-Fisher M. , Shahidi M. , Pemberton K. , Wind S. , de Bono J. , Spicer J. F. 
Published: August 2020

e14541 Background: BIBW 2992 is an oral, potent and irreversible inhibitor of both EGFR and HER2 receptor tyrosine kinases. The efficacy of cytotoxic agents can be enhanced by erbB inhibition. The primary objective of this Phase I open- label dose-escalation trial was to determine the maximum tolerated dose (MTD) of BIBW 2992 in combination with weekly paclitaxel. Methods: This study evaluated safety, pharmacokinetics (PK), and anti-tumor efficacy of daily BIBW 2992 combined with paclitaxel administered on Days 1, 8 and 15 of a 4-weekly cycle. The dose of paclitaxel was 80 mg/m2, and the BIBW 2992 starting dose was 20 mg, escalated in successive cohorts to 40 then 50 mg. After 6 cycles of combination therapy, patients benefiting and tolerating treatment were eligible to continue single agent BIBW 2992. Results: Sixteen patients with advanced solid tumors expressing erbB receptors and suitable for treatment with a taxane have been enrolled (6 male/10 female; median age: 59 [range: 39–72]; ECOG PS 0/1: 5/11). Two dose-limiting toxicities of fatigue and mucositis occurred at a BIBW 2992 dose of 50 mg. The most frequent adverse events were fatigue, rash, mucositis and diarrhea. Partial responses were seen in patients with non-small cell lung cancer (3), prostate cancer (1), oesophageal cancer (1) and cholangiocarcinoma (1). Eight patients have remained on treatment beyond 4 cycles. The PK data of paclitaxel (with and without BIBW 2992 administration) as well as of BIBW 2992 at steady state (in combination with paclitaxel) will be described. Conclusions: A BIBW 2992 dose of 40 mg daily in combination with weekly paclitaxel 80 mg/m2 is the likely recommended dose for Phase II study. Promising anti-tumor activity was seen with this combination. The addition of bevacizumab to BIBW 2992 with 80 mg/m2 weekly paclitaxel is now being evaluated. Adverse events of BIBW 2992 combined with paclitaxel were generally mild to moderate and manageable. [Table: see text]
Vascular endothelial growth factor receptor-2 (VEGFr-2) genetic polymorphisms as predictors to antiangiogenic therapy
Authors: Jurado J. , Ortega J. A. , Iglesias P. , García-Puche J. L. , Belon J. 
Published: August 2020

e14561 Background: Vascular endothelial growth factor (VEGF) and its receptors (VEGFr-2) have important roles in angiogenesis, predicting risk and prognosis in several solids tumor. VEGFr-2 located on chromosome 4 (4q11-q12) is organized into 30 exons separated by 29 introns. Recently the VEGF-2578 AA and VEGF-1154 AA genotypes were associated with a superior median overall survival when using bevacizumab in metastatic breast cancer. We investigated the association of VEGFr-2 polymorphisms to efficacy and toxicity in patients with antiangiogenic therapy. Methods: We performed genotype for selected VEGFr-2 polymorphisms in promoter regions 5’UTR, 3’UTR; in exons 7, 8, 9, 11, 16, 17, 18, 21, 27, 30 and introns 9, 17, 20. DNA was extracted from venous blood of 44 patients with non-curable solid tumors who have received treatment with bevacizumab (B) N=20 (45%) or raf kinase inhibitors 55%; vatalanib (PTK-787) N=3, sunitinib (SU011248) N=6, sorafenib (BAY 43–9006) N= 13, ZD6474 N=1 and AMG706 N= 1. Kaplan-Meier survival analysis was used to assess the association between VEGFr-2 staining and either progression-free survival (PFS) or overall survival (OS). Results: 44 patients have received a median of 6 (1–19) cycles of treatment, 72% was used simultaneously with QT. According to the criteria of NCI-CTC the severe toxicity G3–4 occurred in 47%, 9% with a definite suspension of the drug. The toxicity was not associated with VEGFr-2 genotypes. Efficacy; 5/44 patients (11%) had complete response and 11/ 44 (22%) partial responses by RECIST criteria. With a median follow up of 12 months, the ILP was 8.5 months dt (5.8). The analysis of VEGFr-2 polymorphisms identifies the variant AA of the intron-20 rs2219471 with a significant difference in PFS and OS regarding their ancestral variant AG. Conclusions: Our data suggest that VEGFR polymorphism can be a predictor of clinical outcomes in antiangiogenic therapy. No significant financial relationships to disclose.