bluuebunny/crossref_metadata_2025 huggingface dataset:
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.
Critical evaluation of the role of oxaliplatin- and irinotecan-based regimens as first-line chemotherapy in advanced colorectal cancer (CRC)
Authors: Carnaghi C. , Rimassa L. , Zuradelli M. , Morenghi E. , Torri V. , Tronconi M. C. , Pressiani T. , Santoro A.
Published: March 2020

13562

Background: Until recently, 5-fluorouracil (5-FU) has been the mainstay of treatment for advanced CRC. In the last years, irinotecan and oxaliplatin have been shown to improve survival in combination with 5-FU. It is unclear if this improvement requires the use of these agents as first-line treatment or their sequential use during the course of disease. Methods: In order to assess the impact on prognosis of the first-line chemotherapy regimen, we retrospectively reviewed the outcome of all patients (pts) with advanced CRC treated at our insitution from May 1997 to December 2003. During this period our standard first-line chemotherapy moved from 5-FU and folinic acid (FA) to FOLFIRI to FOLFOX regimens. We analyzed changes in overall survival over time according to administered treatments. Results: From May 1997 to December 2003, 376 consecutive pts with advanced CRC were treated at our institution, 118 from 1997 to 1999, 135 from 2000 to 2001, 123 from 2002 to 2003. Patient characteristics did not vary over time for the 3 cohorts: median age was 62 years (range 26–83), 58% of pts were male, 72% had single metatastic site, liver was the main disease site (72%). In the first cohort (1997–99) the standard first-line treatment was 5-FU/FA, in the second (2000–01) FOLFIRI, and in the third (2002–03) FOLFOX. The number of pts who underwent 1, 2 o 3 lines of treatment for metastatic disease was similar for the 3 cohorts. The median overall survival was 21.4 months (95% CI 19.3–23.3). As shown below, no statistically significant differences were observed among the cohorts. Conclusions: Our retrospective analysis shows that the use of oxaliplatin and irinotecan has pushed the overall median survival to 21 months. The outcome of pts has been similar during the period 1997–2003 despite the shift in standard first-line treatment from 5-FU/FA to FOLFIRI to FOLFOX. These results are reasonably due to the sequential use of all the active regimens. [Table: see text]

No significant financial relationships to disclose.
Retrospective review of toxicities and response of two commonly used regimens (FOLFOX6 and XELOX) in stage IV colorectal cancer
Authors: Mullane M. , Lad T. , Cleveland B. , Yim B. , Tamkus D. , Osafo D.
Published: March 2020

13568

Background: Oxaliplatin and 5FU based regimens have become standard first line treatment for stage IV colorectal cancer. At our institution predominately the regimens FOLFOX6 (oxaliplatin/infusional 5FU via a central venous catheter) and XELOX (oxaliplatin/ capecitabine given orally) are used. We performed a retrospective review of 40 patients to see if any differences, primarily in toxicities, but also in response, emerged. Methods: . Twenty consecutive patients with Stage IV colorectal cancer who received FOLFOX6 as initial therapy and twenty consecutive patients who received initial XELOX, with the oxaliplatin given via a peripheral IV, were analyzed. The decision to administer FOLFOX6 or XELOX was not made for clinical reasons, but came about from logistical difficulties placing central venous catheters in our institution, due to cost and operating time. Comparisons were performed with a Mann Whitney test. The two groups were well matched in terms of sex, age, and performance status. Response evaluations were made based on RECIST criteria. Results: Toxicities compared in the two groups (FOLFOX6 v. XELOX) were gastrointestinal, >Gr. II (5 v. 20%); dermatologic, >Gr. III (0 v. 35%); bone marrow, > Gr. II (15 v. 20%); neurologic, >Gr. III peripheral neuropathy (10 v. 10%); and development of arm pain/discomfort (0 v. 30%). The two toxicities reaching a significant difference, with the higher incidence from XELOX, were > Grade II dermatitis (p= 0.03) and development of arm pain (p=0.05). The response rate of FOLFOX6 was 75% and that for XELOX was 55% (p value of 0.144). Conclusions: Our conclusions from this analysis are that the two regimens are comparable in terms of response, but that FOLFOX6 may be preferable in order to avoid severe dermatitis and if XELOX is the treatment choice, serious consideration should given to administer the oxaliplatin via a central catheter.

No significant financial relationships to disclose.
In-depth analysis of high effectivity in phase II study (irinotecan and doxifluridine, an intermediate form of capecitabine) for metastatic colorectal cancer: MCSGO, Colorectal Cancer Treatment Group
Authors: Kato T. , Miyake Y. , Ikenaga M. , Mishima H. , Fukunaga M. , Murata K. , Ota H. , Sekimoto M. , Sakamoto J. , Monden M.
Published: March 2020

13570

Background: We have already reported the results of the Phase II multicenter study [a combination of irinotecan (CPT-11) and doxifluridine (5’-DFUR) for MCRC], including the survival period (2006 GI Cancer Symposium Abst #130). In this report, we mention the details of the treatment introduced after this combination and discuss the response observed in each metastatic lesion. Methods: The subjects were 60 CPT-11 naive patients with MCRC. They had a measurable disease that satisfied the RECIST criteria and had gone through not more than one regimen of chemotherapy (median age: 64 years (28–74); male/female: 37/23; ECOG PS 0/1: 52/8; main location of metastatic lesion: liver 31, lung 13, lymph node 15). CPT-11 (150 mg/m2, i.v.) was administered on days 1 and 15, 5’-DFUR (800 mg/body, p.p.) was administered day 3 to 15 and day 17 to 28. One cycle of treatment consisted of 5 weeks. No requirements were imposed on the follow-up treatment. Results: According to the results of this regimen, ORR was 40% [23/60, CR;1, PR;23], OS was 20.5 months, and PFS was 5.9 months. The main NCI-CTC grade 3–4 adverse events included neutropenia (28.3%), fatigue (11.6%), nausea (8.3%), vomiting (6.6%), and diarrhea (5.0%).A follow-up therapy regimen was selected and implemented by each investigator. The main regimens adopted for the 49 patients who received this combination as a 1st line therapy included FOLFOX (n=10), hepatic arterial infusion (HAI) (n=10), and others (n=13). 16 patients received no follow-up therapy. The duration of treatment was 5.0 months in the case of 2nd line therapy and 3.0 months in the case of 3rd line therapy. The response rate by metastatic lesion was as follows: liver 35.4% (11/31, PR;11), lung 53.5% (7/13, CR;1, PR;6), and lymph node 46.6% (7/15, PR;7). Conclusions: The combination of CPT-11 and 5’-DFUR is effective in treating lung metastasis and HAI in treating liver metastasis was suggested.

No significant financial relationships to disclose.
Phase II clinical trials of combination S-1 plus low-dose twice weekly cisplatin for advanced or recurrent gastric cancer
Authors: Tsuji A. , Morita S. , Uchida M. , Okamoto K. , Morita M. , Horimi T.
Published: March 2020

14013

Background: We reported the efficacy and safety of combined S-1 + low-dose consecutive cisplatin therapy for advanced or recurrent gastric cancer (Clin Cancer Res. 10:1664–9, 2004). However, this procedure was complicated because the daily dosage of CDDP was necessary. We confirmed that 6 mg/m2 dosage of twice weekly Cisplatin were maintained equal protein binding Pt concentration after daily treatment of 3 mg/m2 dosage of Cisplatin. We examined an effect and safety of a Combination S-1 plus low-dose twice weekly Cisplatin treatment. Methods: All the subjects were admitted to the hospital as inpatients for the first 2 weeks of therapy. S-1 was administered orally daily at the daily dose level of 80 mg/m2 (administered in two divided doses). Cisplatin 6 mg/m2 was administered by intravenous drip infusion over 30 minutes on 2days of the week (Day1 and Day4). Each treatment cycle consisted of 4 weeks of drug administration followed by a 2-week drug-free period (6 weeks in total). Results: 32 patients were enroled in this study. The response was rated as complete response in 1 case, partial response in 24 cases and stable disease in 5 cases. The response rate was 78.1% (25/32). The median survival time was 10.3 months. The response rate did not differ between previously untreated patients and patients who had received prior treatment. The major adverse reactions to the therapy were bone marrow suppression and gastrointestinal symptoms. The total incidence of grade 3 or more severe adverse reactions was 15.6% (5/32). Conclusion: Combination S-1 + low-dose twice weekly Cisplatin therapy thus appears to be highly efficacious and safe, offers promise as a useful treatment strategy even at outpatient clinics. [Table: see text]

No significant financial relationships to disclose.
Oxaliplatin/CF/5-FU versus paclitaxel/CF/5-FU in patients with advanced gastric cancer: A phase II clinical trial
Authors: Lin T. , Xu F. , Wang S. , He Y. , Tian W. , Guan Z.
Published: March 2020

14014

Background: Although many randomized trials of chemotherapy for advanced gastric cancer have been reported during the past two decades, no standard regimens worldwide have been established yet. Now Paclitaxel and Oxaliplatin have shown promising activity in advanced gastric cancer. We prospectively evaluated toxicity, efficacy and survival of Oxaliplatin /CF/5-FU versus Paclitaxel/CF/5-FU. Methods: Metastatic or locally advanced gastric cancer; performance status (PS) 0–2. Patients (pts) were enrolled and randomized into arm A with Oxaliplatin 100mg/m2, 5-FU 400 mg/m2 bolus, FA 200 mg/m2 2h, 5-FU 2500 mg/m2 46h, q2w or into arm B with Paclitaxel 80 mg/m2, 5-FU 400 mg/m2 bolus, FA 200 mg/m2 2h, 5-FU 2500 mg/m2 46h, q2w. Results: From 2000 to 2005, (A/B) 46/43 pts were enrolled into this study. Median age (52/50 y), gender, PS, localization and numbers of metastatic sites were comparable for both arms. Pts who were not chemotherapy naive in A/B (% of pts) were 41.3/33.3. All pts were eligible and evaluable for toxicity and response. Overall response (CR+PR) rate for A/B (% of pts): 37.0/47.2 (p<0.05), tumor control rate (CR+PR+SD) 76.1/69.4(p<0.05). Median time to progression (TTP) were for A/B: 6.0 and 3.2 months. And median survival time for A/B were 13.4 and 13.8 months. Grade 3/4 toxicities were for A/B (% of pts): neutropenia 10.9/5.6, thrombocytopenia 4.3/2.8, anemia 0/2.8, vomiting 8.7/2.8, neurotoxic 0/2. No treatment-related death occurred in A/B. Conclusions: Oxaliplatin /CF/5-FU and Paclitaxel/CF/5-FU are both effective and safe in advanced or metastatic gastric cancer. Though Oxaliplatin /CF/5-FU had better tumor control rate and median TTP, there was no difference between the arms in the median survival time.

No significant financial relationships to disclose.
A phase II study of alternating chemotherapy with CDDP/ 5FU/ folinic acid (FA) and epirubicin (E)/ docetaxel (T) (CF-ET regimen) as first line therapy for patients (pts) with metastatic gastric cancer (MGC)
Authors: Kirchner H. H. , Panagiotou P. , Jordan O. , Hamann S. , Sosada M.
Published: March 2020

14021

Background: Active single agents in MGC are 5FU, CDDP, Anthracyclines, Taxanes and irinotecan. Combinations consisting of docetaxel, cisplatin, 5FU (TPF) and epirubicin, cisplatin, 5FU (ECF) have been investigated and both have shown activity and improvement of survival. However, the most efficient regimen is not yet defined. Methods: Chemotherapy-naive Patients with histologically confirmed MGC and measurable lesions were enrolled in this study. They received CDDP 35 mg/m2 iv on day (d) 1, 2, 15 and 16, 5FU 2000 mg/m2 continuous infusion (ci) d 1, 8, 15 and 22, FA 200 mg/m2 iv d 1, 8, 15 and 22 and E 60 mg/m2 d 29 and 43, T 60 mg/m2 d29 and 43 q d 57. Pts with at least one completed cycle were eligible. Objectives of this study were to evaluate the response rate, toxicity, PFS and OAS of CF-ET. Results: Between 2002 and 2005 34 pts (22 male and 9 female) aged 31 - 77 years (median 61) entered. The total number of treatment cycles was 56, mean 1.8 (1 - 5). 31 pts were eligible. 9 pts had complete response; 11 pts had partial response, 4 pts had stable disease, 7 pts had progressive disease and 3 pts were not evaluable. The overall response rate was 64.5%. The median response duration was 6.1 months (2 - 29.4). The overall survival was 11.4 months (2.6 - 43.6). Grade 3/4 toxicities were leukopenia 41/37.5%, neutropenia 16/82%, thrombocytopenia 23.2/0%, neutropenia related fever was observed in 4 cycles. No severe organ toxicities nor toxic death was seen. Conclusions: The alternating CF-ET regimen showed significant efficacy with prolonged survival. The ET-part of the regimen induced severe but manageable haematological toxicities. The results require further evaluation in a randomized phase III - trial.

No significant financial relationships to disclose.
Phase II study of a combination of S-1 and weekly paclitaxel in patient with advanced or recurrent gastric cancer
Authors: Ueda Y. , Yamagishi H. , Ichikawa D. , Morii J. , Kakihara N. , Yamashita T. , Aragane H. , Nishi H. , Chigusa A. , Sakamoto J.
Published: March 2020

14033

Background: Based on the results of our phase I study on a combination of S-1 (tegafur, oxonic acid, and CDHP) and weekly paclitaxel (PTX) for advanced or recurrent gastric cancer (ARGC) (Ueda et al, ASCO 2004), we conducted a multi-center phase II study to prospectively evaluate efficacy, QOL, and toxicity of S-1 plus weekly PTX in patients with ARGC. Methods: Eligibility included patients with histologically-proven ARGC, 20–80 years old, having a ECOG performance status (PS) of 0–2 and adequate organ functions, and having received no prior chemotherapy except postoperative adjuvant therapies without taxanes. S-1 was given orally at a dose of 80 mg/m2/day for 14 consecutive days (days 1–14) followed by a 2-week rest. PTX was administered weekly as a 1-hour intravenous infusion on days 1, 8, and 15. This treatment was repeated every 4-weeks as one cycle. Results: Fifty-four patients with measurable lesions (RECIST) were enrolled between Feb. 2004 and Nov. 2005. Histologically, a half of the patients had differentiated type and the other patients had undifferentiated type adenocarcinoma. The median age was 61 (range, 38–78). Three-fourths were male patients. The PS was 0/1/2 in 47/6/1 patients respectively. Thirty nine were primary cases and 15 were recurrent cases after gastrectomy. Treatment was terminated in two patients for toxicities and in one patient for refusal during the first cycle; thus compliance of 94.4%. A total of 254 cycles were administered (median 4.7, range 2–14), and 45 patients were assessable efficacy and toxicity until Dec. 2005. In these 45 assessable patients, 2 CRs and 27 PRs were obtained, resulting in an overall response rate of 64.4%. Twelve pts (26.7%) had stable disease, and 4 pts (8.9%) progressed. The tumor control rate was 91.1%. Conclusions: The combination of S-1 and weekly PTX is highly active for ARGC, and can be given safely with good tolerance and convenience profile. It is a candidate for the standard regimen and expected to contribute to better prognosis and QOL in ARGC patients.

No significant financial relationships to disclose.
A phase II trial of the epothilone B analog BMS-247550 in patients (pts) with hepatobiliary cancer (HBC): An updated analysis
Authors: Singh D. A. , Taber D. , Ansari R. , Lenz H. J. , Agamah E. , Nattam S. , Wade-Oliver K. , Kasza K. , Vokes E. E. , Kindler H. L.
Published: March 2020

14050

Background: BMS-247550 is a semi-synthetic analog of epothilone B that induces mitotic arrest at G2M by microtubule stabilization. We previously reported (Proc ASCO 2003) a RR of 17% in HBC and present our final analysis. Methods: Pts with histologically confirmed hepatocellular cancer (HCC), gallbladder cancer (GB) and cholangiocarcinoma (C) were eligible. Pts had no prior chemotherapy, PS 0–2 and ≤ grade 1 neuropathy. Pts received BMS-247550 40mg/m2 intravenously over 3 hours every 21 days. A Simon, optimal two-stage design was employed. We proceeded to the 2nd stage of accrual after 3 confirmed PRs in the first 21 pts. Primary endpoint: Response rate (RR). Results: From 1/02–4/05, 54 pts (52% male) were enrolled, 53 pts evaluable for toxicity, 48 pts evaluable for response. 1 pt was ineligible due to incorrect diagnosis but evaluated for toxicity. Pt characteristics: median age 65 (range 19–88); ECOG performance status 0(48%), 1(48%), 2(4%); HCC (38%), GB (40%), C (22%); metastatic disease (75%); 129 cycles were administered (median 2; range 1–14). There were 3 Gr 5 toxicities: 1 pt died unexpectedly 48 hours within drug administration; 1 complication of neutropenic fever; 1 found unresponsive after fall. Gr 3–4 toxicities (% pts): neutropenia (39%), neutropenic fever (6%), anemia (6%), thrombocytopenia (2%), nausea (13%), transaminase elevation (9%), fatigue (7%), and hypersensitivity (4%). Neuropathy: Gr 3–4 (5%); Gr 1–2 (39%). 3 pts were removed from study due to persistent neuropathy. Responses: 8% PR (2 HCC, 1 GB, 1C); 56% SD. 4/7 HCC pts received ≥ 10 cycles. Median survival: 7 months [95% CI (5.0, 10.8)]; PFS: 2.6 months [95% CI [1.4, 4.1)]; Conclusions: Despite initial tumor responses and a few pts with prolonged SD in HCC, BMS-247550 does not appear to have clinically significant activity in HBC. Supported by NCI grant N01-CM-17102.

[Table: see text]
Pilot study of capecitabine combined with celecoxib (CapCel) as second-line treatment for advanced pancreatic (P) and biliary tree (BT) cancer
Authors: Gelibter A. , Milella M. , Malaguti P. , De Marco S. , Ruggeri E. , Carlini P. , Pino M. , Nuzzo C. , Sternberg C. N. , Cognetti F.
Published: March 2020

14055

Background: COX-2 is overexpressed during cancer progression in several solid tumors, including P and BT, and constitutes an attractive therapeutic target. Selective COX-2 inhibitors, such as celecoxib, have been successfully combined with fluoropyrimidine-based regimens, resulting in a lower-than-expected hematologic, GI, and skin toxicity rate. Methods: Advanced P or BT patients (pts), progressing after first-line treatment, were eligible for the study. Capecitabine was administered at 1000 mg/m2 b.i.d. on days 1–14 q3 weeks; celecoxib was administered at 200 mg b.i.d. continuously starting on day 1. PFS was the primary endpoint. ORR, toxicity, OS, clinical benefit (CB), and QoL were secondary endpoints. Assuming that a rate of PFS >15% at 3 mos would be considered of interest in this pt population, an accrual of 28 pts was planned according to the exact single-stage phase II design described by A’Herne. Results: To date, 25 pts have been accrued (M/F: 11/14; median age: 64 yrs, range 39–75; P/BT: 18/7; PS 0–1/2–3: 19/6). All pts completed at least 1 treatment cycle (median: 3, range 1–9). Twenty-three pts are currently evaluable for response: 1 PR and 1 MR (duration: 33 and 27+ wks) were observed, both in pts with P; 5 additional pts showed SD (duration: 10+, 21, 22+, 27, and 42 wks); the remaining 16 pts had PD. All pts and 83 cycles are evaluable for toxicity. Hematological toxicity was negligible; only 4 pts experienced G3 non-hematological toxicities: diarrhea (2 pts, 2 cycles), skin toxicity (1 pt, resolved with treatment delay), asthenia (1 pt, 2 cycles), and GI bleeding (1 pt, requiring treatment interruption after cycle 1). To date, 19 pts have progressed and 15 pts have died: median PFS is 11 wks (range 3–42) and median OS is 16 wks (range 4–54). Nineteen pts had elevated CA19.9 serum levels at baseline, which decreased of > 25% during treatment in 7 pts, remained stable in 3 pts, and increased in 9 pts. The evaluation of CB and QoL is ongoing. Conclusions: CapCel is a feasible and well-tolerated, fully oral, treatment regimen for advanced P and BT patients, which shows activity, albeit modest, even in a second-line setting. Further evaluation of this therapeutic strategy is warranted.

No significant financial relationships to disclose.
Cetuximab, intensity-modulated radiotherapy (IMRT), and twice-weekly gemcitabine for pancreatic adenocarcinoma
Authors: Pipas J. M. , Zaki B. , Suriawinata A. A. , Tsapakos M. J. , Ripple G. H. , Colacchio T. A. , Sutton J. E. , Gordon S. R. , Kasibhatla M. S. , Barth R. J.
Published: March 2020

14056

Background: Epidermal growth factor receptor (EGFR) is over expressed in pancreatic cancer. Cetuximab is an EGFR-antagonist which has synergy with gemcitabine (gem) and radiation. Gem is a potent radiosensitizer. We are conducting a Phase II trial of cetuximab with IMRT and twice-weekly gem. Eligibility includes stage I-III adenocarcinoma, with EGFR staining by immunohistochemistry. Pretreatment evaluation includes chest/abdomen CT scan and laparoscopy. Methods: Cetuximab 400 mg/m2 IV load was given over two hours. One week later, treatment continued with weekly cetuximab 250mg/m2 IV over one hour, and gem 50mg/m2 IV twice-weekly for twelve doses, concurrent with IMRT given in 28 daily fractions to 54Gy. Cetuximab/gem was given prior to that day’s IMRT. GI prophylaxis was with a proton pump inhibitor. Patients were considered for resection 4–8 weeks following therapy. Results: Ten patients enrolled to date, median age 70 years (range 54–83). Ninety percent of tumors were EGFR positive (range 1+ to 3+). At presentation, three tumors were unresectable, three borderline resectable and four resectable. One patient was removed from study following cetuximab anaphylaxis. Eight patients experienced grade III-IV hematotoxicity. Two patients had ischemic stroke in the backdrop of infection, one from stent obstruction/cholangitis, the other during neutropenic fever. One of these patients (age 81) died. Autopsy revealed severe atherosclerotic disease and evidence of prior strokes. Eight patients were evaluable for response. No patient had local progression. One patient had liver metastases post treatment. Two patients (25%) exhibited partial response. All others had stable disease. EGFR over expression did not predict response. Six patients went on to margin (−) resection, including one patient each with borderline resectable and unresectable disease prior to therapy. At median follow up of 8.5 months, there were no recurrences. Conclusions: Therapy yields modest efficacy and high resectability rates in patients with pancreatic cancer. Downstaging of tumor can occur in some patients. Toxicity may in part reflect the elderly patient demographic. Planned accrual is 48 patients.

[Table: see text]
Phase II study of S-1 in patients with gemcitabine resistant advanced pancreatic carcinoma
Authors: Sudo K. , Yamaguchi T. , Ishihara T. , Nakamura K. , Saisho H.
Published: March 2020

14070

Background: S-1 is an oral fluoropyrimidine derivative with reported response rate of 21.1∼37.5% for advanced pancreatic carcinoma (Ueno, Oncology 2005; Furuse, ASCO 2005). The primary objective of this study was to assess the efficacy and safety of S-1 in patients with gemcitabine resistant advanced pancreatic carcinoma. Methods: Patients with histologically or cytologically proven, metastatic pancreatic carcinoma who had failed prior chemotherapy with gemcitabine were eligible for this study. Other eligibility criteria included an ECOG performance status (PS) of 2 or less; an age of at least 20 years; adequate organ function; and written informed consent. S-1 was administered orally at a dose of 40 mg/m2 twice daily for 28 days, followed by a 14-day rest period. Treatment was repeated every 6 weeks until disease progression. Results: Seventeen patients were enrolled with the following characteristics: median age 67 (range 40–75); male/female = 9/8; ECOG PS 0/1/2 = 1/8/8. All patients were included in analysis. Treatment was generally well tolerated and no life threatening toxicity was observed. Grade 3–4 toxicities were anorexia (17.6%) and fatigue (5.9%). Common grade 1–2 toxicities were anorexia (35.3%), anemia (35.3%), leukocytopenia (29.4%) and diarrhea (23.5%). Three patients were discontinued S-1 because of toxicities. Out of the 17 eligible patients, 3 patients (17.6%) achieved a partial response and 5 patients (29.4%) had stable disease. A marked decrease (≥50%) in tumor markers was observed in 5 (29.4%) of the patients. (CA 19–9 in 3 patients, CEA in 1 patient, DUPAN-2 in 1 patient) The median progression-free survival and the median survival time from the date of initiation of S-1 were 4.1 months (95% CI, 2.0 to 6.2 months) and 5.7 months (95% CI, 2.6 to 8.7 months), respectively. Conclusions: S-1 is well tolerated and active in patients with gemcitabine resistant advanced pancreatic carcinoma. Further investigation of this treatment appears warranted.

No significant financial relationships to disclose.
RP101 improves the efficacy of gemcitabine in treating pancreatic carcinoma
Authors: Haenel M. , Quietzsch D. , Heinemann V. , Boeck S. , Schmid R. M. , Liebert A. , Fahrig R.
Published: March 2020

14075

Background: (E)-5-(2-bromovinyl)-2’-deoxyuridine (BVDU, RP101), was initially tested in a phase 1 pilot study in pancreatic cancer. Patients (n=13) received gemcitabine (1000 mg/m2), cisplatin (50 mg/m2) and RP101 (500 mg/day). The median survival was 447 days and the TTP was 280 days. Ten of the 13 pts lived longer than one year, 4 nearly two years. Based on these promising results a phase 2 study was initiated to explore varying doses of RP101 used with a fixed dose of GEM. Methods: Pts with advanced pancreatic adenocarcinoma were eligible for treatment in this single arm study. 22 pts (16 stage IV and 5 stage III) received GEM 1000 mg/m2 on days 1, 8 and 15 of a 28-day schedule. RP101 treatment, at doses of 500, 625, 750, 875 or 1000 mg/day, was on the same day and for three days after chemotherapy. The mean age was 60 years and 73% of pts were males. Results: The results are based on interim data from an ongoing study and patients at the 2 highest dose groups are still being treated. All RP101 dose groups were combined for analyses, which included all enrolled pts. The data on the 6-month survival status show that 41% are alive; 23% dead; and 36% followed less than 6 months. The median survival (95% CI) is 7.1 months (5.9, not calculated) and 14/22 pts (64%) are still alive. The 6 month survival rate (95% CI) is 0.69 (0.52, 0.85). This compares very favorably with a large recent randomized trial in which pts who received GEM alone had a median survival (95%CI) of 5.9 months (5.1–6.7). PFS and TTP continue to be assessed in this ongoing trial. There appears to be a dose dependent increase in peak GEM levels as a function of the dose of RP101. To date, adverse events are consistent with those observed with GEM or the underlying disease. Conclusion: RP101 may improve treatment of advanced pancreatic cancer when used with gemcitabine. Updated data on survival, PFS, and safety will be presented based on available data.

[Table: see text]
Irofulven (IROF) combined with oxaliplatin (OXA) in advanced hepatocellular carcinoma (HCC) patients (pts): Phase I study (preliminary results)
Authors: Goldwasser F. , Houédé N. , Bertheault-Cvitkovic F. , Misset J. , Raymond E. , Benettaib B. , Kahatt C. , MacDonald J. R. , Weems G.
Published: March 2020

14082

Background: IROF, a semisynthetic derivative of the natural product illudin S, is a novel DNA binding agent that has demonstrated antitumor activity in pts with a variety of chemoresistant tumors. Currently available systemic chemotherapy offers limited benefit to HCC pts. Evidence of IROF activity in HCC was seen with IROF 11 mg/m2 daily x4 every 28 days (Stuart et al, ASCO 2003), and every other week dosing schedules (Falcon et al, ASCO 2004). Preclinically, IROF exhibits additive and synergistic antitumor activity in combination with OXA. Methods: Dose escalation was performed in pts with HCC and other advanced malignancies in this Phase I study. Dose levels (DL) were OXA (mg/m2)/IROF (mg/kg): DLI: 40/0.3; DLII: 40/0.4; DLIII: 50/0.4; DLIV: 60/0.4; DLV: 70/0.4; DLVI: 80/0.4. OXA (2-hour infusion) was followed by IROF (30-min infusion) on Days 1 and 15 every 28 days. Results: Of the 41 pts treated, 8 had HCC, 2 treated at DLI and 6 at DLVI. Median age of these 8 pts was 48 years; PS (ECOG) 0/1: 1/7; median AFP 1253 ug/L (range 16–39760); 3 pts had a history of hepatitis (B/C : 2/1) and 2 of cirrhosis; 3 had prior chemotherapy and 3 chemoembolization; all but one had metastatic disease. Safety: A median of 3 cycles was given (range 1+ to 5+). One pt experienced grade (G) 3 vomiting, 5 pts G1–2 asthenia and nausea, 4 G3 thrombocytopenia and 3 G3 neutropenia. Efficacy: Activity was seen in 6 of the 8 HCC pts, (DLI: 1; DLVI: 5); 1 confirmed PR with AFP decrease from 1250 to 1.9 (99.8%; DLVI) and PFS of 3.5+ months; 1 PR, non-confirmed (42% AFP decrease, 20741 to 11974; DLVI) with PFS of 3.6 months, and 4 SD (DLI: 1; DLVI: 3) were observed with a median duration of 3.6 months (3.2–6.0 +); 3 SD pts (3.8, 3.9 and 3.2+ month duration) had 12%, 52% and 36% AFP decrease respectively. Based on activity in the whole cohort and in the absence of an MTD, DLVI (80/0.4) was selected as the recommended dose. Conclusions: Combined IROF/OXA shows substantial activity and is well tolerated in advanced HCC pts. Additional HCC patients will be included at the RD to evaluate the efficacy of IROF/OXA in this indication.

[Table: see text]