bluuebunny/crossref_metadata_2025_split huggingface dataset:
EZN-2968, a novel hypoxia-inducible factor-1α (HIF-1α) messenger ribonucleic acid (mRNA) antagonist: Results of a phase I, pharmacokinetic (PK), dose-escalation study of daily administration in patients (pts) with advanced malignancies
Authors: Patnaik A. , Chiorean E. G. , Tolcher A. , Papadopoulos K. , Beeram M. , Kee D. , Waddell M. , Gilles E. , Buchbinder A. 
Published: August 2020

2564 Background: HIF-1 is a transcription factor that regulates expression of many key genes, notably those switching cell metabolism to anaerobic glycolysis and inducing neovascularization in response to hypoxia. Increased HIF-1α levels are associated with poor prognosis in several neoplasms. EZN-2968 is a potent locked nucleic acid antisense oligonucleotide suppressing HIF-1α mRNA translation in vitro (IC50 ∼1–5 nM). Methods: This study was designed to determine the safety, tolerability, PK, maximum tolerated dose, recommended dose, and preliminary evidence of antitumor activity of EZN-2968. Pts with advanced malignancies were treated with EZN-2968 administered as a daily 2-hr IV infusion x 5 days every 4 weeks using a 3+3 dose-escalating design. Dose escalation was based on toxicities observed during Cycle 1. Results: 19 pts (11 men; median age = 60 y [47–79 y]) were treated with EZN-2968 doses of 0.5 (3 pts), 0.8 (3 pts), 1.2 (3 pts), 1.8 (4 pts), 2.7 (3 pts), and 4.1 (3 pts) mg/kg/day. Tumor types included colorectal cancer (7 pts); renal cancer (4 pts); soft-tissue sarcoma (STS; 2 pts); angiosarcoma (1 pt); melanoma (1 pt); and breast, ovarian, pancreatic, and prostate cancers (1 pt each). No dose-limiting toxicities were observed. The most common adverse events (Aes) were vomiting (32%); fatigue (26%); and anemia, diarrhea, nausea, and tumor pain (each 21%). Most Aes were Grade 1 or 2. Plasma PK for Day 1 is tabulated below. Stable disease was observed for 1 pt with angiosarcoma (28 wks) and 1 pt with renal cancer (12 wks). Conclusions: EZN-2968 was well tolerated in previously treated pts with advanced malignancies. PK data do not show accumulation of EZN-2968. Dose escalation is ongoing; final results will be presented at the meeting. Durable stable disease has been observed. [Table: see text] [Table: see text]
Ixabepilone and lapatinib for HER2-positive advanced breast cancer: Preclinical rationale and phase I trial
Authors: Mainwaring P. N. , Nguyen T. , Price G. , Venter D. 
Published: August 2020

2582 Trastuzumab with or without taxanes are the cytotoxic therapies of choice for advanced Her-2 positive breast cancer. Ixabepilone and lapatinib have demonstrated clinical efficacy in advanced breast cancer that is resistant to taxanes and trastuzumab. We have compared the therapeutic potential of ixabepilone, lapatinib, paclitaxel and trastuzumab, in vitro, prior to commencing a phase I clinical trial. Three different breast cancer cell lines SK-BR3, BT-474 and MCF-7 (control; non-Her-2 amplified), were seeded 96-well plates, cultured for 24 hours and different concentrations of ixabepilone or paclitaxel and trastuzumab or lapatinib were added. Experiments were performed in triplicate. A MTT viability assay was used to measure the activity of live cells after 0, 3, 24, 48 and 120 hours. The cells and vehicle control wells were averaged and normalized to 100% for comparison to the average value of the 6 replicate wells graphed over time for each cell line, drug concentration and cell density. Student-t test was used to determine the level of significance comparing the 0 hour time point in a pair-wise, pooled variance manner to each other time point. Paclitaxel + trastuzumab significantly reduced proliferation p < 0.001 at 120 hrs; Paclitaxel + lapatinib significantly reduced proliferation p < 0.001 at 120 hrs; Ixabepilone + trastuzumab significantly reduced proliferation p < 0.001 at 120 hrs; Ixabepilone + lapatinib significantly reduced proliferation p < 0.001 at 120 hrs; Dose response curves were clearly evident for all combinations. Of note proliferation was reduced earlier and at lower drug concentrations with lapatinib combinations than with trastuzumab combinations. The drugs whose efficacy was proven in MCF-7 cells were studied in detail on the xCELLigence cell analysis system. These data recapitulated the MTT data and provided in depth detail of the rate of drug action. An international multicentre phase I trial of Ixabepilone with lapatinib ± capecitabine has commenced in patients with Her-2 positive taxane and trastuzumab resistant advanced breast cancer. Toxicity has been as previously described with fatigue, arthralgias, onycholysis and rash occurring. No DLTs have occurred. RECIST responses have been confirmed in 2 of the first 3 patients enrolled. [Table: see text]
A phase I trial of adoptive transfer of allogeneic natural killer (NK) cells in patients (pts) with advanced non-small cell lung cancer (NSCLC)
Authors: Iliopoulou E. G. , Kountourakis P. , Karamouzis M. V. , Doufexis D. , Ardavanis A. , Baxevanis C. N. , Rigatos G. , Papamichail M. , Perez S. A. 
Published: August 2020

3001 Background: HLA-mismatched NK cells have been found effective in acute myeloid leukemia pts. Preclinical studies revealed that activated NK cells massively infiltrate lung tissue and improve recipient survival, suggesting a potential role in lung cancer therapeutics. We performed this phase I trial to evaluate safety and antitumor responses of allogeneic, in vitro activated and expanded NK cells in combination with chemotherapy (C) in pts with advanced NSCLC. Methods: Pts with unresectable locally advanced/metastatic NSCLC receiving 1st/2nd line C were eligible. Two relative donors for each pt were selected based on their HLA and KIR typing. CD56+ cells were isolated from 150ml of donor peripheral blood and cultured for 20–23 days with 20ng/ml interleukin-15 and 10-5M hydrocortisone. Activated and expanded NK cells, after sterility, phenotype, and function testing, were diluted in 500ml N/S 0.9% with 2% human serum albumin and administered i.v. for 1 hour 2 days after previous and 1 week prior next C. Premedication with corticosteroids and/or H1 inhibitors was allowed. The number of NK cells to be injected was up to 2x1011/dose for up to 4 doses. Pts and donors signed detailed informed consent. Results: Between 11/2007 and 11/2008 16 pts (performance status 0–1) were enrolled; 1 pt had rapid disease progression before treatment. Pts characteristics: M/F 12/4; histology: adenocarcinoma/squamous cell carcinoma 13/3; stage IIIb/IV 2/14; 1st/2nd line treatment 13/3; median age 64 years (range, 50–71). The number of doses administered was 2 (N=9 pts), 3 (N=2 pts), or 4 (N=4 pts). The number of cells injected varied from 0.2–29x106/Kg (mean 7.4x106±7.7x106). During and after injection of NK cells no side effect (local or systemic) was observed. With a median follow-up of 6 months (range, 1–14) 3 pts with partial response and 7 pts with disease stabilization were recorded. Conclusions: Adoptive transfer of allogeneic, in vitro activated and expanded NK cells in combination with chemotherapy is safe, even at the highest dose administered. Based on these encouraging results a randomized phase II trial is further justified. No significant financial relationships to disclose.
Overcoming tumor antigen anergy in human malignancies using the novel indeolamine 2,3-dioxygenase (IDO) enzyme inhibitor, 1-methyl-D-tryptophan (1MT)
Authors: Soliman H. H. , Antonia S. , Sullivan D. , Vanahanian N. , Link C. 
Published: August 2020

3004 Background: The limited effect of cancer immunotherapy is due to the tumor's ability to induce host anergy towards its antigens. The enzyme indoleamine 2,3-dioxygenase (IDO) is thought to play a key role in anergy induction. IDO metabolizes tryptophan (trp) into immunosuppressive metabolites such as kynurenine (kyn). The oral IDO inhibitor, 1-methyl-D-tryptophan (1MT), was studied in preclinical models. The preclinical data support the activity of 1-MT in preventing T-cell anergy in TDLN, slowing growth of LLC mouse xenografts, and synergizing with chemotherapy in regression of autochthonous breast tumors in MMTV-Neu mice. This led to a phase I first-in-man trial using 1-MT in solid tumors. Methods: This is a phase I study treating adults with refractory solid malignancies. Patients are treated with up to 6 consecutive 28-day cycles starting at 200mg once daily. A 3+3 dose escalation to MTD is used. PK analysis, weekly labs, and CT scans every 2 cycles were done. Correlative studies include serum kyn/trp levels, T-reg cell quantification by flow, tumor IDO expression by IHC, and humoral immune response using a proprietary tumor antigen microarray. Results: Ten pts have recieved 1-MT at 200mg daily. Tumors treated included 1 esophageal, 1 peritoneal, 3 melanomas, 2 sarcomas, and 3 NSCLC. PK results show good bioavailability and a t1/2 of 2–4 hrs. Of the 7 evaluable pts, 4 had SD and 3 had PD. Attributable toxicities were 1 case of grade 1 fatigue and 2 cases of grade 2 hypophysitis. Both cases occurred in pts who received prior immunotherapies. Six new pts without prior immunotherapy were enrolled at the 200mg dose level. Five pts remain on treatment currently. Three pts had decreased T-reg cells after treatment with 1MT and 4 pts showed marked CRP increases. One pt had increased autoantibody titers against 3 tumor antigens compared to baseline. Conclusions: 1-MT appears to be an active, orally bioavailable, and reasonably well tolerated immunomodulator at 200mg daily. Development of hypophysitis in 2 patients indicates the drug can break tolerance resulting in autoimmunity. Enrollment to the trial continues. Future trials will combine 1-MT with other immunotherapies and chemotherapies for solid tumors. [Table: see text]
Phase I adjuvant trial of multi-epitope p53 vaccine for patients with squamous cell carcinoma of the head and neck (SCCHN): A preliminary report
Authors: Andrade P. , Deleo A. , Visus C. , Butterfield L. , Argiris A. , Ferris R. L. 
Published: August 2020

3012 Background: Alteration in the tumor suppressor protein, p53, is one of the most common events in human cancers. Since most mutations of p53 are associated with accumulation of p53, the nonmutated portions of protein are readily accessible to degradation into wild type (wt) sequence peptides for immune recognition by T lymphocytes. Methods: A phase I trial was conducted in stage I-IVa patients (pts) with SCCHN with no active disease using autologous dendritic cells (DC) loaded with two HLA-A*0201-restricted T cell-defined p53 peptides alone (Arm 1, 5 pts), plus either a wt p53 helper peptide (Arm 2, 5 pts) or nonspecific helper peptide (dervied from tetanus toxoid, Arm 3, 6 pts). The accrual goal is 24 patients, divided into the 3 arms. Each pt received 3 intranodal vaccinations at 2-week intervals. The primary endpoint was immunological response using ELISPOT, tetramer or delayed type hypersensitivity (DTH)reactions to p53 peptides. Results: 16 pts have been vaccinated so far. Erythema or hematoma were observed at vaccine injection sites in two pts. At 15-mo median follow-up, 11/16 pts are alive without evidence of disease, 2 developed disease recurrence, and 1 pt developed a second primary lung cancer. Two have died of unrelated causes. Immunological analyses of the SCCHN patients’ responses to immunization indicate responses to both HLA-A2 binding peptides. Tetramer frequencies for p53-specific CTL or IFN-gamma ELISPOT assays indicated a 5/16 responders. Ongoing correlative analyses include characterization of human papillomavirus (HPV) infection, HLA, antigen processing machinery, and staining with soluble T cell receptor for HLA-A2-p53 peptide complexes on tumor cells. Conclusions: Adjuvant p53 peptide-loaded DC-based vaccination is feasible and safe in pts with SCCHN. A phase II wt p53-based vaccine trial will be proposed based on the most efficacious regimen used in this trial. No significant financial relationships to disclose.
Elimination of cancer stem cells (CD133+/EpCAM+) from malignant ascites by the trifunctional antibody catumaxomab: Results from a pivotal phase II/III study
Authors: Lindhofer H. , Schoberth A. , Pelster D. , Hess J. , Herold J. , Jäger M. 
Published: August 2020

3014 Background: Putative cancer stems cells (CSCs) are defined as “tumor-initiating cells” that have the capacity to self-renew and to give rise to the variety of differentiated cells found in the malignancy. The CD133 membrane glycoprotein represents a CSC marker that has been previously demonstrated to be capable of identifying a cancer-initiating subpopulation in brain tumors, melanoma, and EpCAM+ solid tumors. The trifunctional anti-EpCAM x anti-CD3 antibody catumaxomab efficiently eliminates tumor cells from the peritoneal fluid of malignant ascites (MA) patients as demonstrated in a pivotal phase II/III trial (Parsons et al., ASCO 2008). Here we report on the presence of CD133+/EpCAM+ putative CSCs in MA and, more importantly, on the elimination of this cell population from the peritoneal fluid of MA patients by means of catumaxomab therapy. Methods: 18 CTX-refractory patients with MA caused by a variety of primary carcinoma diseases (i.e., ovarian, pancreas, and gastric cancer) were analyzed for the presence CD133+/EpCAM+ cells in peritoneal fluids by means of CD133+/EpCAM+ double staining on cytospin preparations. Analyses were performed before, 2 days after the first, and 1 day after the last catumaxomab infusion, respectively. Double-stained cytospin preparations were evaluated with a computerized image analysis system. Results: Before therapeutic intervention, CD133+/EpCAM+ cells were detected in the peritoneal fluids of 14 from 18 patients suffering from MA. After the 1st infusion of catumaxomab (10μg), 9 of these 14 patients showed complete elimination of the CD133+/EpCAM+ cells. After 4 i.p. catumaxomab infusions (10μg day 0, 20μg day 3, 50μg day 7 and 150μg day 10) the CD133+/EpCAM+ cells were completely eliminated from the peritoneal fluids of all 14 MA patients. Conclusions: In a preliminary monitoring study, putative CSCs (CD133+/EpCAM+) were present in peritoneal fluids of 78 % of analyzed MA patients with different underlying primary tumor entities. Catumaxomab efficiently destroyed CD133+/EpCAM+ cells within peritoneal fluids of MA patients. Consequently, catumaxomab-based therapeutic measures may offer an additional treatment opportunity to eliminate CSCs in EpCAM+ malignancies. [Table: see text]
Phase II experience with MDX-1106 (Ono-4538), an anti-PD-1 monoclonal antibody, in patients with selected refractory or relapsed malignancies
Authors: Brahmer J. R. , Topalian S. L. , Powderly J. , Wollner I. , Picus J. , Drake C. G. , Stankevich E. , Korman A. , Pardoll D. , Lowy I. 
Published: August 2020

3018 Background: Programmed death-1 (PD-1), an inhibitory receptor expressed on activated T cells, may suppress antitumor immunity. This expansion cohort in a phase I/II trial of MDX-1106, a fully human IgG4 antibody blocking PD-1, sought to further evaluate the safety and activity of the 10 mg/kg dose. Other objectives included evaluation of pharmacokinetics (PK) and immunological effects. Methods: Patients (pts) with treatment refractory metastatic non-small cell lung cancer (NSCLC), renal cell carcinoma (RCC), colon cancer (CC), melanoma (MEL), or prostate cancer (CRPC), and no history of autoimmune disease received a single infusion of MDX-1106 at 10 mg/kg. Disease status was evaluated at week (wk) 8 by RECIST criteria. Pts with stable disease or lesional responses could receive additional MDX-1106 at wks 12 and 16. Those with PR/CR were observed without retreatment. Results: 21 pts (5 CC, 2 NSCLC, 8 MEL, 5 HRPC, 1 RCC) were treated from 10/07 to present, and 6 were retreated. No MDX-1106 related SAEs occurred. One pt developed arthritic symptoms requiring treatment, and 2 pts had asymptomatic TSH elevation. One pt with RCC had a PR after 3 doses, lasting 5+ months (mo). Lesional regressions (“mixed response”) were seen in 2 MEL pts; to date, one has received 7 doses of MDX-1106 over 15 mo without serious toxicity. Biopsy of a regressing MEL lymph node metastasis showed a moderately increased and selective CD8+ T cell infiltrate post treatment. The median serum t 1/2 of MDX-1106 was 20.6 days, which was roughly 50% longer than observed for lower doses. There was no evidence of immunogenicity based on HAHA development. Interestingly, in contrast to PK results, flow cytometric analysis demonstrated sustained occupancy of 60–80% PD-1 molecules on T cells for at least 3 mo following a single dose. Analyses of circulating lymphocyte subsets and tumor B7-H1 expression are in progress. Conclusions: Intermittent dosing of MDX-1106 at 10 mg/kg demonstrated clinical activity against RCC and MEL without serious toxicity. Therapy with MDX-1106 to enhance endogenous antitumor immunity, either alone or combined with other immunological therapies, warrants further study. [Table: see text]
Cellular immune suppression in cancer patients and its implication for dendritic cell therapy
Authors: Nesselhut J. , Lorenzen D. R. , Marx D. , Chang R. Y. , Matthes C. , Hildenbrand B. , Schneider E. M. , Nesselhut T. 
Published: August 2020

3028 Background: The treatment of human cancer with monocyte-derived dendritic cells (MoDC) is a promising and innovative approach. However, many of the treated patients fail to respond to therapy. The reduced clinical antitumor response may be due to an inflammatory immune-suppressive tumor microenvironment. Regulatory T-cells (T-reg) and other cells with suppressive potential can promote an immune suppressive tumor microenvironment and thus play an important role in regulation of the immune response. Methods: Whole blood from n=100 cancer patients with various tumor types and from n=30 healthy donors were analysed by flow cytometry. CD4+ lymphocytes with immune suppressive potential were characterized by analysing the expression of CD25, CD39, CD127. Results: We found a significantly higher proportion of CD25+/CD39+ and of CD25+/CD127low T-helper cells in the blood of cancer patients as compared to healthy donors. This may indicate two different types of T-reg involved in immune suppression in cancer patients. Treatment of patients with metronomic chemotherapy induced a down-regulation of these cells. Interestingly, we found a subpopulation of cells within the lymphocyte gate characterized by CD2high and CD86 expression in cancer patients with very advanced stage, similar to such normally found in hemaphagocytic lymphohistiocytosis (HLH) patients characterized by exceeding high plasma concentration of IFN-g and IL-10 (Schneider et al. 2002). These cells can be down-regulated by treatment with a tetradecapeptide (Ezrin) known to act as an immune modulator with anti-viral activity leading to reduction of inflammatory cytokines. Conclusions: An efficient induction of a clinical antitumor response requires both a polarization of MoDC in a TH1 direction as well as changing an immune suppressive tumor microenvironment. For the first time, we identified HLH associated cells in advanced cancer patients. As HLH is characterized by hyperinflammation, these cells may indicate an inflammatory tumor microenvironment. Thus, anti-inflammatory therapy should be considered as co-treatment with immunotherapy with dendritic cells for down-regulation of immune suppressive cells (T-reg, CD2high/CD86+ cells) to promote a clinical antitumor response. No significant financial relationships to disclose.
Pharmacodynamic (PD) evaluation of LY2181308 in patients with metastatic malignancies
Authors: Talbot D. C. , Davies J. , Olsen A. , Andre V. , Lahn M. , Powell E. , Kadam S. , de Bono J. , McHugh P. , Ranson M. 
Published: August 2020

3507 Background: Survivin is an inhibitor of apoptosis and its overexpression in cancer has been associated with poor survival. LY2181308 (LY), a novel modified antisense oligonucleotide is a specific inhibitor of survivin. The safety and PK profile of LY from this first-in-human study was presented at ASCO 2008. We now present the PD data from this trial. Methods: Patients with advanced or metastatic malignancies who had failed previous anti-tumor treatments were enrolled. Three consecutive IV loading doses given over 3 hours were followed by weekly maintenance doses. Pre- and post-dosing biopsies were mandated to test for evidence of modification of the target at doses where a PD effect was expected. Biopsies were taken 48 hours after the last loading dose by CT-guided fine needle biopsy. Tumor tissue was paraffin-embedded for immunohistochemistry (IHC) and survivin gene expression. Given the finite amount of biopsy material, the quantification of survivin protein was prioritized. In addition, at one site, pre- and post-dosing endobronchial sampling was conducted in NSCLC patients, with the aim of quantifying levels of native survivin protein, and assessing changes in cell cycle profile in freshly isolated tumor cells using FACS analysis. Results: Out of the 34 patients enrolled, 22 patients had a pre- and posttreatment biopsy. Results from IHC indicated that survivin expression was reduced in the nucleus and cytoplasm in 11/17 and 5/14 evaluable pairs, respectively. LY was detected in neoplastic and non-neoplastic tumor cells in 5/16 and 15/16 evaluable pairs respectively. Gene expression analysis indicated a reduction in survivin expression by 20% to 50% in 11/15 evaluable pairs. Analysis of the fresh tumor material from endobronchial sampling revealed that 2 out of 3 patients with NSCLC had a near-complete elimination of survivin-positive cells accompanied by an increase in the fraction of cells with a sub-G1 DNA content, consistent with cell death. Conclusions: In this study, we were able to demonstrate the presence of the ASO in tumor tissue and confirm a reduction in survivin protein and gene expression. These findings demonstrate the proof of principle of antitumor activity of LY and provide the rationale for phase II studies. [Table: see text]