bluuebunny/crossref_metadata_2025_split huggingface dataset:
Influence of single agent gemcitabine (GEM) schedule on the pattern of response and toxicity in patients with advanced pancreas, lung and breast carcinoma: A systematic review
Authors: Barrajon E. , Lopez A. , Esquerdo G. 
Published: March 2020

13009 Background: Dose dense chemotherapy has been advocated as a way to improve results in patients with cancer. Increasing dose (and the area under the curve of concentration-time, AUC) may increase response and toxicity, limiting clinical benefit. For phase-specific agents such as GEM, different schedules with the same dose and AUC may produce different patterns of efficacy and toxicity. Partial comparisons between schedules in clinical trials are not able to design optimal schedules. A systematic analysis of all different schedules of GEM, integrating clinical, pharmacodynamic and pharmacokinetic data in a mathematical model may provide an optimum. Methods: Clinical trials of single agent GEM in advanced pancreas, lung and breast carcinoma have been searched in PubMed, references of published clinical trials, and presentations in cancer meetings. Prognostic factors (age, sex, sex, performance status, previous chemotherapy, stage), schedule details (dose, time and frequency of infusions), response rate and toxicity (hematological, mucosal, skin and diarrhea) were analyzed in a multivariate model. In vitro data (concentration and time of exposure) and pharmacokinetic/pharmacodynamic data were included in the model, estimating the AUC above a concentration threshold (AUCt) obtained for every clinical schedule. Results: Ninety five clinical trials including 7917 patients with cancer of the pancreas (39 trials), lung (45 trials) or breast cancer (11 trials) were pooled. GEM was administered at doses of 90–2800 mg/m2 (median 1000 mg/m2) infused in 0.5–24 hours (median 0.5 h). Except for 1 schedule, treatment was repeated for 1–7 consecutive weeks (median 3) followed by a 2 week rest period. Response rate was 2.7–33.3% (median 8%) for pancreas, 0–38.5% (median 18.5%) for lung and 0–37.1% (median 20%) for breast cancer. Epithelial toxicity was inferior to hematological toxicity (grade 3/4: 0% vs 11% for leucopenia). A mathematical model was applied to 24 different schedules. Conclusions: GEM schedules in literature show great homogeneity, most of them 1000 mg/m2 for 3 consecutive weeks followed by a 2 week rest period. The model allows simulations to optimize concentration over 12 nM. No significant financial relationships to disclose.
Combined treatment with immunotherapy and chemotherapy using endoscopic ultrasonography guided injection for locally advanced pancreatic carcinoma
Authors: Nonogaki K. , Hirooka Y. , Itoh A. , Kawashima H. , Ohmiya N. , Niwa Y. , Goto H. , Yamamoto K. , Takamatsu J. , Yokokawa K. 
Published: March 2020

13503 Background: Dendritic cells (DCs) play a pivotal role in T cell-mediated immunity. Usually, mature DCs were cultured using resected tumor tissue, but for inoperable cases, this method is impractical. The injection of immature DCs into the tumor after appropriate chemotherapy is reasonable, if DCs come to maturity capturing the specific cancer antigen . The aim of this study is to assess the toxicity and efficacy of combined treatment with immunotherapy and chemotherapy for locally advanced pancreatic carcinoma. Methods: Five patients with pathologically confirmed pancreatic ductal carcinoma using EUS-FNA were enrolled, median age 56 years (range, 46–70 years). All cases without distant metastasis were diagnosed as surgically unresectable . Patients underwent leukapheresis, immature DCs were prepared from peripheral blood by a culture with granulocyte macrophage colony-stimulating factor and interleukin 4. Lymphokine-activated killer (LAK) were also prepared from peripheral blood. Immature DCs were injected biweekly in the mass by endoscopic ultrasound-guided fine needle injection (EUS-FNI), LAK were administered intravenously. Patients received the treatment of gemcitabine 1000 mg / m2 by intravenous injection 3 days before the immunotherapy. One course with 6 times combined therapy was continued until the judgment of progressive diseases (PD) was given. The toxicity and efficacy of this treatment were assessed. We also assessed whether tumor associated antigen (TAA)-specific IFN-?producing cells increase after treatment. Results: Hematological toxicity occurred in one case, leucopenia of grade 2. No severe toxicities of grade 3 to 4 occurred. One had a partial response (PR), stable disease (SD) was observed in 2 patients for more than 6 months (long-term SD). PR patient could undergo curative operation after this therapy. The number of TAA-specific IFN-?producing cells in PR patient increased 12-fold higher than that seen before treatments. Conclusions: These results support the safety and efficacy of combined treatment with immunotherapy and chemotherapy for locally advanced pancreatic ductal carcinoma. This treatment may be a useful for the treatment of pancreatic ductal carcinoma. No significant financial relationships to disclose.
A phase I/II study of an antitumor vaccination using α (1,3) galactosyltransferase expressing allogeneic tumor cells in pancreatic cancer
Authors: Oyama Y. , Talamonti M. , Mulcahy M. , Gonda E. , Burt R. K. , Vahanian N. N. , Bell R. , Tennant L. , Ramsey W. J. , Adrian T. , Link C. 
Published: March 2020

13512 Background: Prognosis of pancreatic cancer remains poor despite surgical resection. In a phase I trial, we examined the safety and feasibility of antitumor vaccination in Pts with surgically resected pancreatic cancer with two irradiated genetically altered human pancreatic cancer cell lines engineered to express xenotransplantation antigens by retroviral transfer of the murine a(1,3) galactosyltrasferase gene {HyperAcute Pancreatic Cancer Vaccine (HAPa)}. Methods: Pts had undergone complete surgical resection for stage IA to IIB pancreatic adenocarcinoma, ECOG PS≤2, no immunosuppressive drug use and an adequate organ function were eligible. Various adjuvant treatments were allowed prior to the start of HAPa according to the institutional preferences (5FU/radiation, cisplatin/gemicitabine followed by 5FU/radiation, 5FU/radiation followed by gemicitabine or gemicitabine/capecitabine/bevasizumab/radiation). Six Pts were scheduled to receive 12 every two week-intradermal injections (initial priming dose followed by 11 boost doses). The first cohort (Pts 1–3) was to receive at lower doses (2 × 108 cells priming and 1 x 108 cells boost). The second cohort (Pts 4–6) was to receive at higher doses (5 x 10^8 cells priming and 3 x 10^8 cells boost). Toxicity was assessed using the CTC v3.0. Results: To date, 6 Pts, 3 males, 3 females, median age 59 (range 50–66) were treated. Two Pts completed all 12 injections. Others received 9, 6, 6 and 4 injections, respectively. To date no serious adverse events can be attributed to the vaccine. Adverse events (≤CTC grade 2) attributable to the vaccine include injection site pain/discomfort and local skin reaction in all Pts. Other adverse events (≤grade 2) include hyperkalemia, fever and increased LDH levels in one Pt. One Pt with non-malignant hepatic lesions at the time of initial surgery was removed from the study after confirmation of metastatic disease in the liver. At this point the median 6.5 (range 9–4) months in the study all remaining (5/6) patients have no evidence of recurrent disease. Conclusions: Preliminary data indicate that antitumor vaccination with genetically altered allogeneic human pancreatic cancer cells expressing a(1, 3) galactosyltrasferase is safe and feasible [Table: see text]
A phase II study of FolateImmune (EC90 with GP1–0100 adjuvant followed by EC17) with low dose cytokines interleukin-2 (IL-2) and interferon-α (IFN-α) in patients with refractory or metastatic cancer
Authors: Messmann R. , Amato R. , Hernandez-McClain J. , Conley B. , Rogers H. , Lu J. , Low P. , Bever S. , Morgenstern D. 
Published: March 2020

13516 Background: FolateImmune is a folate-receptor (FR)-targeted immunotherapy that induces an immune response against tumor cells by marking them with a folate-hapten conjugate. The conjugate is specifically designed to target FR, which is over-expressed in a variety of cancers. FolateImmune therapy is comprised of a vaccine fluorescein conjugate (EC90), an adjuvant (GP-0100), and a folate-hapten conjugate (EC17). Patients (pts) receive a series of subcutaneous (SQ) injections of EC90 vaccine to stimulate the production of antibodies to the fluorescein-hapten, followed by SQ injections of EC17, which forms a molecular bridge between the tumor cell and the endogenous circulating anti-fluorescein IgG antibody. This is thought to initiate an Fc-mediated immune response leading to antibody-dependent cellular cytotoxicity and/or phagocytosis. IL-2 and IFN are utilized at low doses (7 MIU and 3 MIU, respectively) to further promote an immune response. The Phase Ib objective is to determine the safety of EC90 vaccine/EC17 folate-targeted therapy in combination with IL-2 and IFN. The previous phase I trial explored the safety of FolateImmune without cytokines. Methods: This phase 1b safety study treated eligible patients with FolateImmune therapy at dose levels of 1.2 mg EC90 and EC17 of 0.3 mg/kg. Results: As of Jan 2, 2007, all patients have tolerated therapy without significant toxicity. Grade 1–2 toxicity included: chills, fever, and nausea. One patient has had a minor response and continues on study. Laboratory studies revealed decline in circulating FR+ cells. Of 6 pts enrolled, 5 had a pathologic classification of renal cell cancer (RCC). Conclusion: Preliminary data suggest that FolateImmune therapy, with the addition of low dose cytokines, may be administered in a safe and well-tolerated manner. Phase II trials are planned for RCC. No significant financial relationships to disclose.
Activation of the AMPK regulated metabolic stress response by a small molecule HER2/EGFR tyrosine kinase inhibitor protects cardiac myocytes from apoptotic stimuli
Authors: Bacus S. S. , Hill J. E. , Trusk P. , Seger R. , Spector N. L. 
Published: March 2020

14000 Background: The HER2 receptor tyrosine kinase is a survival factor for human cardiomyocytes, providing a potential explanation for the increased incidence of cardiomyopathy associated with anti-HER2 monoclonal antibody trastuzumab. Here we show that GW2974, a HER2/EGFR TKI, but not trastuzumab activates AMP kinase (AMPK), initiating a metabolic stress response in human cardiomyocytes that protects against TNFa induced cell death. GW2974 stimulates calcium dependent fatty acid oxidation in vitro resulting in upregulation of ATP and in myocardium of GW2974 treated rodents. Methods: Western blot: p-Akt, p-Erk1/2, p-AMPKa and p- eEF2 (Cell Signaling); ERRa, ERR? (R&D Systems); PGC-1 (Chemicon); MCAD (Cayman Chemicals); Heregulin, NF?B, and Actin (Sigma). ATP was performed utilizing a bioluminescence assay kit H52 (Roche). Lipid staining was done with Oil Red O (Sigma). Cells: Au565 breast cancer and primary human cardiomyocytes (HMC) were grown in RPMI supplemented with 15% BFS treatments. BAPTA/AM and Compound C (Calbiochem); GW2974 and TNFa (Sigma); trastuzumab (Genentech). Results: Our results show that treatment with GW2974 activates catabolic pathways by activation of AMPK. AMPK is a key regulator in mitochondrial energy producing pathways in human cardiac cells. Phosphorylation of AMPK resulted in phosphorylation of eEF2, upregulation of ERRa and PGC-1 and upregulation of ATP levels. AMPK activation depends on Ca++ as the calcium chelation abolished it. Trastuzumab and Gleevec failed to activate AMPK survival pathways. In addition, GW2974 protected cardiac cells from TNFa killing, whereas treatment with TNFa and trastuzumab resulted in pervasive cellular death. Inhibition of AMPK by Compound C or siRNA resulted in cardiomyocyte killing. Conclusion: Activation of AMPK and its effects on metabolic pathways and energy production in HMC may explain the apparent reduced risk of cardiotoxicity associated with HER2 TKI compared with trastuzumab in treating patients with HER2 overexpressing breast cancers. Although activation of AMPK protected normal cardiac myocytes, this effect appears to be lethal to sensitive HER2 overexpressing breast cancer cells, which are “addicted” to glycolysis. No significant financial relationships to disclose.
Phase I trial of intratumoral administration of reovirus type 3 with radiation in patients with advanced malignancies
Authors: Vidal-Boixader L. , Karavasilis V. , Beirne D. , Twigger K. , White C. , Pandha H. , Nutting C. , de Bono J. , Melcher A. , Harrington K. 
Published: March 2020

14009 Background: Reoviruses are RNA viruses that replicate preferentially in cells with aberrant Ras-pathway signaling. Preclinical data have shown that the combination of reovirus (REO) and radiation (RT) significantly increases RT-induced cytotoxicity. Methods: Patients (pts) with measurable disease amenable to treatment with localised short-course palliative RT were enrolled in cohorts of 3. In the first stage, pts received local tumour RT (20 Gy in 5 fractions) in combination with two intratumoural injections of escalating REO doses to a maximum of 1010 TCID50. If no dose-limiting toxicity (DLT), pts received local tumour RT (36 Gy in 12 fractions) in combination with two, four or six doses of REO at TCID50. Endpoints were safety, viral replication, immunogenicity and antitumoral activity. Results: Eighteen pts have been treated to date with a variety of solid tumours.Two pts, one at the 1 x 109 dose and one at 1 x 1010 refused to receive the second REO injection due to grade 2 flu-like symptoms. Other toxicities have been mild (grade 1–2) and have included fever, sweating, skin erythema. There has been no evidence of exacerbation of the acute RT reaction. Reverse transcription polymerase chain reaction (RT-PCR) studies of blood, urine, stool and sputum on day 8 post-REO administration were negative for viral shedding for all treated pts. The induction of neutralising anti-REO antibodies was attenuated compared with previous experience in pts receiving intravenous infusions. Three pts (oesophageal ,skin squamous and colorectal carcinoma) had significant partial responses. In addition, the pt. with metastatic oesophageal cancer had a volume reduction of 15% in non-irradiated mediastinal disease for more than 6 months. Intratumoral viral replication by electron microscopy and immunohistochemistry of pre- and post-treatment tumour biopsies was performed. Conclusions: The combination of intratumoral REO and radiation is well tolerated. Promising indicators of synergistic effect are observed. Recruitment is ongoing at the last cohort of the trial. No significant financial relationships to disclose.
Phase I evaluation of tipifarnib in combination with low-dose Ara-C (LDAC) in high-risk myelodysplastic syndrome (MDS) or acute myeloid leukemia (AML): Interim results
Authors: Cortes J. E. , Feldman E. J. , Douer D. , Raza A. , Fruchtman S. 
Published: March 2020

14014 Background: Tipifarnib (T) is a farnesyltransferase inhibitor with clinical activity in MDS and AML. LDAC has utility in the elderly with MDS/AML; hence its use in combination with the investigational agent T to improve outcomes is warranted. Methods: The primary objective of this ongoing phase I, dose finding, multicenter, open-label study was to determine the maximum tolerated dose (MTD) based on dose limiting toxicities (DLT) of T+LDAC observed during the first 28 day cycle. MDS (IPSS Int 1, 2 or High) and untreated AML pts (age =75y or =65y with preceding MDS) or relapsed/refractory AML (age >18y) were included. Planned sample size was up to 57 pts with a traditional 3+3 dose escalation and a minimum of 3 pts enrolled per cohort. T (Dose Level 0) was administered initially at 200mg PO BID x 21 days in combination with LDAC 10mg SC BID x 10 days; both repeated every 28 days. Efficacy will be assessed by bone marrow and peripheral blood count studies. Results: 15 pts have been enrolled to date: 2 MDS (Int 1 n=1, High n=1) and 13 AML (7/13 pts with no previous therapy); all 15 pts were evaluable. Mean baseline characteristics for the entire cohort were: age 76.2y, 67% men, Hb 9.4 ± 0.9 g/dL, WBC 8.7 ± 11.3 x 103/μL, platelets 96.8 ± 96.6 x 103/μL. The observed DLT for T+LDAC was generalized rash seen at Dose Level 3. The MTD was therefore determined to be T 300mg and LDAC 15mg. The most common grade 3/4 adverse events were neutropenia, thrombocytopenia, anemia, and rash. Conclusions: These interim findings show the combination of T at 300mg PO BID x 21 days and LDAC at 15mg SC BID x 10 days to be the MTD in this study. Assessment for efficacy is ongoing. [Table: see text] No significant financial relationships to disclose.
Phase I experience with an anti-glycotope monoclonal antibody, RAV12, in recurrent adenocarcinoma
Authors: Burris H. A. , Lewis N. , Rosen L. S. , Jones S. F. , Cohen R. B. , Kunkel L. A. , Stewart S. J. 
Published: March 2020

14017 Background: RAV12 is a high affinity, internalizing, chimeric IgG1 monoclonal antibody (MAb) that binds RAAG12, a novel primate-restricted N-linked carbohydrate epitope present on multiple cell-surface proteins. RAAG12 is variably expressed on normal non-keratinizing epithelia, particularly those of GI origin (cytoplasm and apical membrane), and is not expressed on human tissues from the cardiovascular, endocrine, hematolymphatic, neuromuscular, and central nervous systems. IHC studies demonstrated diffuse membrane staining on > 90% of human colorectal, gastric, and pancreatic adenocarcinoma samples. RAAG12 is distinct from previously reported mucin or Lewis blood group carcinoma-associated carbohydrates. In vitro, RAV12 kills tumor cells by oncosis and facilitates ADCC. Methods: In December 2004, a phase I dose-escalation safety and pharmacokinetics (PK) trial was begun in patients with recurrent (1 to 3 prior treatments) adenocarcinoma. RAV12 was administered weekly x 4, twenty-eight patients have received treatment in the following cohorts: 0.3 mg/kg qw (6), 1.0 mg/kg qw (8), 1.5 mg/kg qw (7), 0.5 mg/kg biw (3), 0.75 mg/kg biw (2), and 0.5 mg/kg tiw (2). Sixteen patients had colorectal, 5 gastroesophageal, 4 pancreatic, 2 lung cancer, and 1 breast cancer. Responses were evaluated on day 42. Results: Preliminary analysis demonstrated dose-dependent PK. Three clinical syndromes associated with drug administration have been observed to date: 1) abdominal cramping pain (21 patients) and diarrhea (18 patients) particularly at the higher doses, 2) asymptomatic, self-limited, generally rapidly reversible excursions of liver function tests (16 patients), and 3) asymptomatic, self-limited, rapidly reversible excursions of pancreatic enzymes (6 patients). One patient (0.3 mg/kg qw), with advanced pancreatic cancer, had a > 50% reduction in CA19–9, continued treatment, and had TTP > 5 months. One patient with colorectal cancer (1.5 mg/kg qw) experienced a durable partial remission, continued treatment, and had TTP > 8 months. Conclusions: RAV12 has activity in recurrent adenocarcinoma. Side effects uncommonly have been dose limiting. The trial continues to define dose/schedule to be recommended for phase 2 testing. No significant financial relationships to disclose.
Inhibition of colon tumor metastasis in an orthotopic nude mouse model with the dual selective Src/Abl kinase inhibitor, AZD0530
Authors: Phillips K. , Parikh N. , Kuwai T. , Green T. , Gallick G. E. 
Published: March 2020

14032 Background: Colorectal cancer is the leading cause of cancer deaths in the USA, largely due to metastatic disease in the liver. The specific activity of the non-receptor protein tyrosine kinase, Src, is increased during colon tumor progression and contributes to metastasis; thus, Src inhibitors may have efficacy in the treatment of advanced-stage colon cancer. AZD0530 is a potent, orally available Src/Abl kinase inhibitor currently in clinical trials. Methods: We examined the effects of AZD0530 alone and in combination with oxaliplatin on two colon tumor cell lines, KM12L4 and LS174T in vitro and in orthotopic nude mouse models. AZD0530 inhibits in vitro proliferation and cellular migration of KM12L4 and LS174T, and decreases phosphorylation of the Src substrates FAK and paxillin in a dose- dependent manner. To examine the ability of AZD0530 to affect colon cancer growth and metastasis in a nude mouse model, we inoculated 1x106 cells into the cecum of nude mice. After 2 weeks, mice were treated with vehicle (n=12), AZD0530 alone (n=13; 25mg/kg/day by oral gavage), oxaliplatin alone (n=13; 5mg/kg/day twice weekly), or AZD0530 and oxaliplatin (n=13). Mice were sacrificed after 4 weeks of treatment. Results: Tumor incidence in all groups of mice was greater than 80%. Mice treated with AZD0530 had an average cecal tumor weight of 0.26 g compared with 0.32 g for control (P=0.24). In contrast, the incidence of liver metastases was reduced by 50% in mice treated with AZD0530 alone or oxaliplatin alone, and no mice developed pathologically evident liver metastases when the combination of inhibitors was used. Furthermore, in mice that developed liver metastases, AZD0530 decreased the size of these metastases 9-fold compared with control. Immunohistochemical analysis of primary cecal tumors demonstrated a decrease in phosphorylated Src (Y418) and FAK (Y861) in AZD0530-treated mice compared with control. Conclusions: These results support further investigation of AZD0530, both alone and in combination, as a new therapeutic strategy for the treatment of advanced colon cancer. No significant financial relationships to disclose.
Effect of bispecific antisense oligos on prostate cancer cell growth
Authors: Rubenstein M. , Tsui P. , Christensen K. A. , Guinan P. 
Published: March 2020

14034 Background: Antisense oligos against TGF-a (MR1), EGFR (MR2), and bcl-2 (MR4) are efficacious against prostate tumors. Methods: To enhance activity “bispecifics” were constructed. A pair recognized TGF-a and EGFR mRNA binding sites (TGF-a/EGFR [MR12] and EGFR/TGF-a [MR21]), another pair EGFR and bcl-2 (EGFR/bcl-2 [MR24] and bcl-2/EGFR [MR42]). Pairs differ in 5’ to 3’ binding site orientation, and were tested in vitro against prostate tumor cells. Following cell attachment, incubations were for 2 days with the agents followed by 2 days in their absence. Results: Bispecifics (6.25uM) are at least as effective as monospecifics and EGFR contributed to most first pair activity. Against PC-3 and LNCaP cells, MR2, MR4, MR12, MR21, MR24 and MR42 significantly inhibited growth. PC-3 cells were then incubated ± a chemotherapeutic agent. With LD50 Cytoxan, MR2, MR4, MR24, MR42 significantly inhibited 47.3, 45.7, 68.3 and 64.9%; with LD50 Taxol MR2, MR4, MR24, MR42 significantly inhibited 49.8, 45.8, 64.1 and 59.2%; and with LD50 DES MR2, MR4, MR24, MR42 significantly inhibited 66.6, 67.6, 64.3 and 67.2% respectively. Each agent significantly increased the inhibition produced by either oligo alone. LNCaP cells were also incubated with mono- and bispecific oligos ± chemotherapeutics. MR2, MR4, MR24, MR42 produced significant inhibitions of 57.4, 58.4, 69.4 and 68.6% for Cytoxan; 70.4, 70.1, 73.6 and 74.0% for Taxol; and 49.8, 50.1, 59.6 and 53.9% respectively for DES. A complete PC-3 experiment compared MR1, MR2, MR4, MR12, MR21, MR24 and MR42 in the presence of LD50 Cytoxan. Each oligo combined with Cytoxan significantly inhibited: MR1 by 51.0, MR2 by 55.0, MR4 by 58.0; MR12 by 56.0; MR21 by 61.1, MR24 by 65.5 and MR42 by 66.0%. Bispecifics directed against two different pathways, MR24 and MR42 were the most effective. A complete LNCaP experiment compared the same series of oligos in the presence of LD50 Cytoxan. Each oligo combined with Cytoxan significantly inhibited: MR1 by 49.0, MR2 by 50.0, MR4 by 53.0; MR12 by 52.0; MR21 by 58.6, MR24 by 53.9 and MR42 by 58.0%. Conclusions: Bispecific oligos significantly advance antisense technology and could play a role treating prostate cancer, particularly when combined with chemotherapy. Bispecifics against proteins associated with different growth pathways may be best. No significant financial relationships to disclose.