bluuebunny/crossref_metadata_2025_split huggingface dataset:
A phase I study of thalidomide, capecitabine and temozolomide (TCT) in advanced cancer
Authors: Khan M. I. , Salvador C. , Schonard C. L. , Taft B. S. , Kloecker G. H. , Laber D. A. 
Published: March 2020

13122 Background: The aim is to develop a novel oral immuno-chemotherapy regimen against advanced cancers. Methods: Patients were enrolled in cohorts of 3 or 6 in a standard phase I design. Thalidomide 100 mg was kept stable for all cohorts. If well tolerated after 1 week, capecitabine and temozolomide (TCT) were given daily without rest and escalated one at a time until dose limiting toxicity (DLT) occurred. If no DLT occurred within 28 days (1 cycle), the following group was enrolled into the next dose level. Results: Twenty-three patients with advanced cancers have been treated in this study. All patients have been evaluated for toxicity and response. Eighty cycles of TCT have been administered (1–13 cycles/patient). Patient characteristics: Median age 59 (31–79), PS ECOG 1 (0–2). Type of cancer: renal (7), bladder (2), pancreatic (2), prostate (2), colon (2), and lung, gastric, synovial sarcoma, angiosarcoma, anal, nasopharyngeal, breast, esophageal (1 each). Prior to TCT, all patients had objective documentation of progressive metastatic disease after a median of 2 therapies (range 0–4). Objective response: Four subjects (17%) achieved partial response (renal 1, gastric 1, prostate 2), and 4 patients (17%) had stable disease (renal 1, colon 1, pancreas 2), adding to a clinical benefit of 34%. Toxicity: Treatment was well tolerated. Common toxicities included grade 3 thromboses 17%; and grade 1–2: hand-foot syndrome, fatigue, sensory neuropathy, nausea, vomiting, and neutropenia. Based on DLT within the first 28 days, the MTD of daily TCT therapy was thalidomide 100 mg, capecitabine 2000 mg and temozolomide 100 mg. With long-term treatment, majority of the patients required dose interruptions due to fatigue, hand-foot syndrome, and neutropenia. Dose level 2.5 was implemented: daily thalidomide and 3-weeks-on 1-week-off capecitabine and temozolomide. Six patients were treated at dose level 2.5 without toxicities. Conclusions: TCT is an effective palliative oral chemo-immunotherapy for patients with advanced cancer. The recommended dose for a phase II trial is dose level 2.5, including thalidomide 100 mg daily, capecitabine 2000 mg/day and temozolomide 100 mg/day three-weeks on and one-week off regimen. [Table: see text]
Hepatic expression of CYP3A4 and CYP3A5 genes in Asians and implications for pharmacokinetic variations during chemotherapy
Authors: R Jada S. , Xiang X. , Zhou Q. , H Li H. , L Ooi L. , Chowbay B. 
Published: March 2020

13124 Background: Hepatic expression of CYP3A4 and CYP3A5 enzymes are important determinants of interindividual variability in chemotherapy. The objective of this study was to genotypically quantitate expression of CYP3A4 and CYP3A5 genes in healthy hepatic tissues from Asian cancer patients undergoing hepatectomy. Methods: Healthy Asian hepatic tissues (Chinese: N = 27; Malay: N = 1; Indian: N = 3) were obtained from the institution’s central tissue repository bank. Messenger RNA was isolated from each tissue sample and reversed transcribed to cDNA followed by real time PCR experiments. Results from these gene expression experiments were normalized against GAPDH transcripts. DNA was also extracted from the hepatocytes and genotyped for four single nucleotide polymorphisms in the CYP3A4 gene (CYP3A4*1B, *4, *5 and *6) and three in the CYP3A5 gene (CYP3A5*1, *3 and *6). Results: CYP3A4 variant forms were absent in all Asian patients. CYP3A5 was polymorphic and genotyping analysis showed that the *1/*1, *1/*3 and *3/*3 genotypes were present in 6%, 52% and 42% of the Asian liver samples, respectively. Liver tissues harbouring the *1/*1 and *1/*3 genotypes showed insignificant CYP3A5 expression pattern (P=0.160). The CYP3A5 mRNA expression levels were approximately 6-fold lower in *3/*3 samples compared with samples carrying at least one *1 allele (*1/*1 + *1/*3). Non-parametric analysis using Kruskal-Wallis test showed that the hepatic expression of CYP3A5 mRNA between liver tissues that harboured at least one *1 allele (*1/*1 + *1/*3) and those carrying homozygous *3/*3 genotype to be highly significantly different (P < 0.007). Conclusions: These results show that polymorphic CYP3A4 isoforms are probably rare in Asians compared with CYP3A5 polymorphisms. This study also suggest that CYP3A5, rather than CYP3A4 could be important for interindividual variations in pharmacokinetics of CYP3A4/5 substrates during chemotherapy in Asians. No significant financial relationships to disclose.
Hydralazine-demethylating systemic therapy for breast cancer
Authors: Safar A. M. , Macleod S. , Klimberg V. , Henry-Tillman R. , Fan C. , Hutchins L. , Makhoul I. 
Published: March 2020

13131 Background: Cancer results from accumulation of gene deregulations. DNA sequence alterations are of unquestioned importance in this process, but are not exclusive. Alterations in gene function unaccounted for by DNA sequence changes (Epigenetic) are quite common, and seem to contribute to carcinogenesis. Abnormal methylation at the promoter region of Tumor Suppressor Genes results in gene transcriptional silencing, and is wide spread in many cancers, including Breast Cancer (BC). Alterations in cancer DNA methylation (DNAm) is among the best characterized epigenetic anomalies. An attractive feature of DNAm is its predisposition to pharmacologic reversal as a therapeutic intervention. Here, we used the cardiovascular drug hydralazine (H) to confirm its proposed demethylating effects and to examine its safety in clinically recommended doses concurrent with chemotherapy. Methods: Operable BC patients undergoing neoadjuvant therapy were enrolled on this study (n = 13). We examined DNAm levels at 2 time points; untreated tumor (biopsy) and H-treated specimen (resection) from the same patient. Global DNAm levels were estimated by examining the methylation level in Alu repeats. The study design conformed to a phase I, dose escalating scheme. H was administered at 50 mg orally TID for the first cohort in addition to standard chemotherapy. Results: H was well tolerated to a maximal dose of 200 mg QID. 1 patient discontinued the drug for headache. 4 patients completed treatment (approx. 4 months) and underwent surgical resection and assessment of methylation. Global Demethylation (defined as decrease of Alu methylation level by ≥5%) was observed in 2/4 [−8% and −9%, respectively]. The remaining patients have undergone surgery but DNA testing not performed as yet (results will be presented in the meeting). Conclusions: Hydralazine is well tolerated in normotensive individuals, in doses ≤ 200 mg/d concurrently with standard chemotherapy for breast cancer. Further, hydralazine produces decrement in DNAm of clinical cancer specimens. Effect of this demethylation on the expression of biologically important genes such as ER and p16 will be evaluated and presented once available. The biologic effect of such alteration in genomic DNAm would require subsequent investigation to prove its therapeutic impact. No significant financial relationships to disclose.
Efficacy of weekly low-dose chemotherapy in elderly women with advanced ovarian cancer: is there an antiangiogenic effect?
Authors: Darwish S. , Bronte G. , Ignoto A. , Piazza D. , Rizzo S. , Russo S. , Carreca I. 
Published: March 2020

13133 Background: In elderly patients decreased functionality of multiple organ systems may affect pharmacokinetics and pharmacodynamics of drugs. For this reason elderly cancer patients experience enhanced susceptibility to common chemotherapy-related adverse events. A way to prevent these effects could be metronomic chemotherapy, which is a variation of dose-dense therapy, with a cumulative dose significantly lower than maximum tolerated dose. Methods: 27 advanced ovarian cancer patients, median age 67 (range 60–86), received low dose weekly continuous chemotherapy until disease progression. All patients were treated with CBDCA AUC 2 mg/ml/min and Docetaxel 35 mg/sqm (adjusted according with Kintzel & Dorr formula) i.v. weekly. Primary endpoints were response rate (RR) and time to treatment failure (TTF). Moreover we considered as secondary endpoints toxicity profile, VEGF values and Quality of Life (QoL) score. RR and TTF were evaluated with RECIST criteria and Kaplan-Meyer formula respectively, toxicity was assessed according to the NCI-CTC. VEGF concentrations were analyzed by ELISA, QoL score was determined using the ADL/IADL and EORTC QLQ-C30 questionnaires, at baseline (T0) and at the end of therapy (T1). Results: median duration of treatment was 39 weeks. 2 Complete Responses (CR) and 5 Partial Responses (PR) were achieved for a 26% RR. Stable Disease was achieved in 18 pts (67%) with a total Clinical Benefit (CB) of 93%. Overall toxicity was very low: haematological G1/2 - 6 pts; gastrointestinal G1 - 8 pts; neurological G1/2 - 5 pts; cutaneous G3 - 1 pt; renal G1 - 1 pt. A mean TTF of 17.4 months was reached. Mean VEGF values (T0): 527 ± 35 pg/ml, (T1): 335 ± 18 pg/ml (p = 0,003). QoL score (T0): 45.2 ± 12, (T1): 47.5 ± 25 (p = 0,06). Conclusions: first results seem to be very encouraging, even if the number of responses is too small and we need to enrol more pts to reach a good statistical evaluation. Nevertheless the use of this “metronomic” schedule shows that VEGF values decrease strongly during the treatment and is maintained also when treatment is discontinued. Thus it suggests a preminent antiangiogenic role of this schedule according with the most recent preclinical and clinical studies. No significant financial relationships to disclose.
The factors affecting objective response in patients with advanced malignant tumor treated with H101, an E1B-55kD deleted oncolytic adenovirus
Authors: Xia H. , Zhao R. , Hu W. , Li Z. , Hu G. , Hu F. 
Published: March 2020

13166 Background: H101 is E1B-55kD deleted oncolytic adenovirus which can selectively replicate in tumor cells. Previous phase I/II clinical trials have shown that H101 has certain anti-tumor effects and is safe when applied to patients by intratumoral injection. The aim of this study is to identify the factors affecting tumor response in patients with advanced malignant tumor treated with H101. Methods: All patients in H101 phase II clinical trial were retrospectively reviewed. They were treated with either H101 alone (group A) or H101 combined with conventional chemotherapy (group B). H101 was administrated by intratumoral injection at the dosage of 5×1011 viral particles, once a day for 5 consecutive days. The objective response was evaluated according to WHO criteria and the adverse events were recorded. All information required for this study was retrieved from the database of H101 phase II clinical trial. Chi square test and stepwise multivariable regression were used for statistic analysis with a significant level of p<0.05. Results: There were 106 evaluable patients in this study, 54 in group A (36 males and 18 females, age: 36–78 years), 52 in group B (35 males and 17 females, age: 18–76 years). The diagnoses of these patients include head & neck cancer (54), breast cancer (13) and others (39). All were in the advanced stage of the disease, and refractory or resistant to chemo and radio therapy. The objective response rate was higher in group B (23.1%) as compared to group A (16.7%). In patients with response (CR or PR), 62.5% of them experienced fever after the injection of H101, in contrast, only 18.9% of the patients without response did so. The difference was statistically significant (p<0.01). In the stepwise multivariable regression analysis, tumor response was used as dependent variable, and the independent variables included demographic data, clinical and pathologic type of the tumor, and treatment regimen. The result revealed that tumor response was positively correlated with the fever after H101 injection (p<0.01). Conclusions: H101 has certain anti-tumor efficacy in patients with advanced malignancies, which might be enhanced by the fever after H101 injection and/or combining with chemotherapy. [Table: see text]
Outcomes and toxicities among octogenarians and nonagenarians with colorectal cancer (crc) treated with chemotherapy or concurrent chemoradiation - a single institution study
Authors: Yu J. , Reddy N. M. , Rajput A. , Smith J. , Yang G. , Fakih M. 
Published: March 2020

13514 Background: Chemotherapy is associated with an improved overall survival with acceptable toxicities in patients ≥ 70 years. However, little to no data exists regarding feasibility and tolerability of chemotherapy and/or radiation in CRC patients ≥ 80 years. The purpose of this study was to identify the trends of increased toxicity in this subgroup of patients. Methods: A retrospective study on patients ≥ 80 yrs treated for CRC with either chemotherapy alone or chemoradiation during the period of 1996- 2005 at Roswell Park Cancer Institute was conducted. Survival analysis was performed using the Kaplan-Meier method. Results: 29 patients were identified. 8 patients were diagnosed as having rectal cancer and received combined chemoradiation. 21 patients had colon cancer and received chemotherapy alone either in the adjuvant or metastatic setting. The median age was 82 years (range: 80–93). The median survival for all stages receiving chemo and/or radiation therapy was 37 months (95% CI: 27–53). The median survival for patients with stage IV disease was 6 months (95% CI: 5–33). Grade III/IV GI toxicities were seen in 59% (95% CI: 37–72%) of patients. Grade III/IV hematologic toxicities were seen in 17% (95% CI: 8–37%) of patients. Empiric chemotherapy dose reductions were implemented, starting the first cycle, in 90% (95% CI: 72–96%)of patients. Therapy had to be withheld in 34% (95% CI: 19–52%) of patients by more than 1 week due to toxicities in the first 2 months of treatment. Conclusions: Our study, demonstrates a higher rate of toxicities than previously reported for patients ≥ 70 years. This has occurred despite an initial dose-reduction in the majority of the treated population (90%). Octogenarian and nonagenarian CRC patients experienced a higher rate of GI toxicities during treatment, some of which were life threatening. This data supports the urgent need to conduct prospective studies to identify treatment recommendations for patients ≥ 80. Data from larger elderly phase II studies with median ages < 80 should not be extrapolated to octogenarians and nonagenarians. No significant financial relationships to disclose.
The Coalition of cancer cooperative groups GI scientific leadership council
Authors: Catalano R. B. , Comis R. L. , O’Connell M. J. 
Published: March 2020

13522 Background: The Coalition of Cancer Cooperative Groups convened the GI Scientific Leadership Council (GI SLC) to provide leadership in establishing and advancing national research priorities for colorectal cancer clinical trials. A key objective was to complement and enhance the scientific programs of the NCI-sponsored GI Intergroup. Methods: A multidisciplinary group of investigators representing the spectrum of diagnostic, therapeutic, and laboratory disciplines engaged in colorectal cancer clinical research was convened in December 2004 to address the most important research opportunities in colorectal cancer, and clinical trials to address those opportunities. In April 2005, the concepts evolved were discussed with representatives of the patient advocate community and the pharmaceutical industry. In December 2005 the GI SLC presented its core research recommendations to more than 100 members of the cancer community. Results: Seven principal cross-cutting themes emerged, as well as ten strategic recommendations to be addressed over the next three years. A portfolio of high priority clinical trials was identified. The GI SLC has prioritized support for three colon cancer surgical adjuvant trials; two rectal cancer surgical adjuvant trials; two colorectal cancer metastatic to the liver trials; two metastatic colorectal trials; and one colon polyp and cancer detection study trial. These will be detailed in our presentation. Conclusions:The GI Scientific Leadership Council represents a novel approach to strengthen colorectal cancer clinical trials and correlative science research in the United States by providing a platform to bring together clinical investigators and translational researchers, the patient advocate community, and the pharmaceutical industry. The GI SLC plans to convene a Cancer Prevention Advisory Group in the first quarter of 2006 and plans to initiate one or more innovative clinical trials in collaboration with industry in 2006. The GI SLC will meet throughout 2006 to develop action plans, review progress towards those plans, and facilitate adoption of the research priorities across the cancer community. No significant financial relationships to disclose.
Evaluation of the thrombospondin-1 analogue ABT-510 in the APCMin/+ mouse intestinal adenoma model
Authors: Joyce D. E. , Mulji G. , Gutierrez L. S. , Castellino F. J. 
Published: March 2020

13545 Background: The extracellular matrix protein Thrombospondin-1 (TSP-1) affects the angiogenic balance in cancer to suppress tumor growth. Exogenous TSP-1 or the peptide derivative ABT-510 (Abbott, Chicago, IL) can reverse this angiogenic switch from adenoma to carcinoma. We evaluated treatment effects of ABT-510 in the APCMin/+ mouse spontaneous intestinal adenoma model. This study determined reduction in intestinal adenoma number after ABT-510 or the combined treatment of ABT-510/bevacizumab (Genentech) compared to no treatment in APCMin/+. Proliferation, vascularity, and dysplasia were also compared. Methods: 90 day old APCMin/+ mice (familial adenomatous polyposis, 5q21 termination), Jackson Laboratory (Bar Harbor, ME)) received drug for three weeks: 1.) ABT-510, 60 mg/Kg/day s.c. pump for 2 weeks then i.p. daily for the last 7 days, 2.) Anti-VEGF antibody bevacizumab 10 mg/Kg i.p. twice per week in combination with ABT-510, and 3.) untreated controls. After 21 days mice were sacrificed, intestines harvested and adenomas enumerated. Immunohistochemistry (PCNA, vWF/CD31) was performed. Studies were IACUC approved. Wilcoxon signed-rank test was used to compare results. Results: Twenty one mice were evaluated with no adverse effects. Comparisons were made to untreated APCMin/+ controls. Untreated controls (N=7) demonstrated a mean of 7.7±1.25 polyps. ABT-510 treated APCMin/+ (N=8) demonstrated a mean of 3.4±1.8 polyps, significantly different from controls (p<0.004). Combined bevacizumab and ABT-510 treatment demonstrated a mean of 4.7 ±3.0 polyps (p<0.008). There was no significant difference between the ABT-510 and combined ABT-510/bevacizumab treated groups. Immunohistochemistry for tumor vascularity (anti-CD31/anti-vWF) and for proliferation (PCNA) demonstrated enhanced vascular and PCNA staining in polyps, but no differences were detected in tumor dysplasia or immunohistochemistry compared across control and treatment groups. Conclusions: Significant reduction in APCMin/+ polyp number was seen with ABT-510 and the combination ABT-510/bevacizumab treatment groups compared to untreated controls. Tumor-specific vascularity and proliferation was characteristically no different across control and treated groups. [Table: see text]
Phase I study of ABT-751 in combination with CAPIRI (capecitabine and irinotecan) and bevacizumab in patients with advanced colorectal cancer
Authors: Messersmith W. A. , Rudek M. A. , Laheru D. , Zhao M. , He P. , Walker R. , Jimeno A. , Purcell W. T. , Donehower R. C. , Hidalgo M. 
Published: March 2020

13553 Background: ABT-751 (A) is an orally (PO) bioavailable sulfonamide with antimitotic properties. We are performing a non-randomized phase I/II dose-escalation study of A in combination with capecitabine (C), irinotecan (I) and bevacizumab (B) to define the maximum tolerated dose (MTD), dose-limiting toxicity (DLT), and pharmacokinetics (PK) in patients with advanced colorectal cancer (1st or 2nd line). Methods: Patients are treated with A QD for 7d (lead-in) and then begin 21-d cycles of treatment with A (QD) and C (BID) d1–14 PO, I d1 IV, and B d1 IV. Dose escalation started at dose level (DL) 1 at A 150 mg, I 200 mg/m2, and C 1600 mg/m2 (total daily dose) and escalated to full dose CAPIRI (I 250 mg/m2, and C 2000 mg/m2) for DL2. B was then added as standard of care at 7.5 mg/kg for DL2b (and later, DL1b). Blood samples were collected for pharmacogenomics (PG), pharmacodynamics (PD), steady-state PK of A and A metabolites when administered alone or in combination with C, I, and B, and PK of I and I metabolites. Serial dynamic contrast MRI’s, before and after the ABT-751 monotherapy lead-in period, are being performed in a subset of subjects. Results: Eight patients have been treated at dose levels 1 (3), 2 (2), and 2b (3). One patient on DL2 experienced g3 transaminitis and another on DL2b had F&N which were dose-limiting. Dose level 1 is being expanded to 6 patients, now with B (DL1b). Other g3/4 toxicities have included g4 neutropenia (1 subject DL2, 1 DL2b). The formation of A glucuronide appears decreased during combination therapy (see table). I PK, PD, and PG samples were collected and analysis is pending. Of 8 subjects, there have been 4 PD and 4 SD after 2 cycles. Conclusions: The combination therapy of A 150 mg and 20% dose-reduced CAPIRI appears well-tolerated. Patient accrual continues at DL1b. [Table: see text] No significant financial relationships to disclose.
Tolerability assessment of urasil-tegafur (UFT)/folinic acid (FA) as concurrent chemoradiation (CRT) in adjuvant rectal cancer treatment
Authors: Atasoy B. M. , Abacioglu U. , Ozgen Z. , Dane F. , Yumuk F. , Akgun Z. , Ozden S. , Mayadagli A. , Turhal S. , Sengoz M. 
Published: March 2020

13559 Background: The objective of the present phase II study was to evaluate the feasibility of UFT and FA as a concomittant CRT administration for rectal cancer in the adjuvant setting. Methods: Between October 2003 and December 2005 thirty-one (10 female; 21 male) patients were treated. All the patients were locally advanced (T2N1–2M0 (2), T3N0M0 (12), T3–4N1M0 (9), T3–4N2M0 (7)) and median age was 62 (range, 21–85). Inclusion criteria were WHO 0–1, age ≥ 18, complete tumor resection, stage T3/4 or N+, adequate CBC, liver function tests and signed informed consent form. RT was performed in 8 weeks following the surgery and the dose was 50.4 Gy given at 1.8 Gy daily. Chemotherapy consisted of UFT (300 mg/m2/day) and FA (30 mg/day) during week-days of radiotherapy and continued 4 cycles with same dose (D1–28/35days) after CRT. Acute toxicity was assessed according to CTC 2.0 criteria. Results: Median follow-up for all patients was 12 months (between 3–27 months). No toxic death occurred. CRT related side effects were diarrhea Gr 2 (25%) and Gr 3 (25%); emesis Gr 2 (29%) and Gr 3 (10%); dysuria Gr 2 (10%) and Gr 3 (10%). All patients completed radiotherapy but 21 out of 31 (67%) continued with UFT/LV until the end of concurrent treatment. The full compliance to the adjuvant CT part was 63%. During the adjuvant CT period there were diarrhea Gr 3–4 (10%), emesis Gr 3 (10%) and no Gr 3–4 hematological toxicity observed during the whole treatment. During the study period none of the patients failed locally, 3 patients developed distant metastases (2 liver, 1 bone), and 3 patients died (1 with disease, 2 without). Two-year disease-free and overall survival rates were 84% and 71%, respectively. Conclusion: The acute and subacute toxicity of CRT with UFT/LV is acceptable and seems comparable to infusional 5-FU based combined modality treatments. No significant financial relationships to disclose.