bluuebunny/crossref_metadata_2025_split huggingface dataset:
A phase I study of TPI 287, a third generation taxane, administered every 21 days in patients with advanced cancer
Authors: Modiano M. , Plezia P. , Baram J. , Catane R. , Cohn A. , Basche M. , Kurman M. , Tapolsky G. , Yancik S. 
Published: March 2020

2569 Background: TPI 287 is a third generation taxane engineered to overcome multi-drug resistance and to bind to mutant tubulin. In preclinical studies, TPI 287 suppressed the growth of multiple human tumor xenografts in nude mice, including xenografts that expressed mdr- 1 and that were resistant to other taxanes. The safety and tolerability of TPI 287 when administered every 21 days was examined in this Phase 1 dose escalation study in patients (pts) with advanced neoplasms. Methods: TPI 287 was administered over 1 hour every 21 days in ascending doses to groups of 3 pts. Treatment cohorts were expanded to 6 pts in the face of dose-limiting toxicity (DLT); pts could remain on study until the development of progressive disease or an intolerable adverse event. DLT was defined as Gr 4 heme toxicity lasting 7 days; febrile neutropenia, Gr 3 thrombocytopenia with bleeding, Gr 3 elevation of transaminases lasting 7 days or any other Gr 3/4 toxicity other than nausea or vomiting. Results: 14 pts (M:F 5:9, median age 58.5, range 49 - 77) were enrolled in 5 dose levels ranging from 56 - 185 mg/m2. Pts’ cancers included colorectal (5 pts), esophageal (2), pancreatic (2), NSCLC (2), breast (2) and ovarian (1). All patients had received prior chemotherapy (median no. prior treatments: 3 (range, 2 - 10). Drug related adverse events included mucositis, vomiting, diarrhea, neutropenia, thrombocytopenia, myalgias and peripheral neuropathy. Only 1 pt. experienced Gr 4 neutropenia. DLT of Gr 3 peripheral sensory neuropathy was observed at a dose of 185 mg/m2. At a dose of 160 mg/m2 no DLT was observed. 1 pt with pancreatic cancer had a confirmed response to TPI 287 that has persisted for 2.5 months and continues as of this writing. PK data reveal that AUC is generally dose linear. At a dose of 126 mg/m2, clearance was 24.7 + 12.2 L/hr/m2 and t1/2 was 10.6 + 7.1 hrs. Conclusions: TPI 287 can be safely administered in a dose of 160 mg/m2 every 21 days. The dose limiting toxicity was Gr 3 peripheral neuropathy. Anti-neoplastic activity was seen in a patient with pancreatic cancer. PK is dose linear and predictable. Several Phase 2 studies of TPI 287 are being planned. No significant financial relationships to disclose.
A phase I pharmacokinetic and pharmacodynamic study of AMG 479, a fully human monoclonal antibody against insulin-like growth factor type 1 receptor (IGF-1R), in advanced solid tumors
Authors: Tolcher A. W. , Rothenberg M. L. , Rodon J. , Delbeke D. , Patnaik A. , Nguyen L. , Young F. , Hwang Y. , Haqq C. , Puzanov I. 
Published: March 2020

3002 Background: Increased IGF-1 signaling mediates tumor proliferation, reduces apoptosis, and correlates with higher incidence and progression of common cancers. AMG 479, a fully human monoclonal antibody against IGF-1R, exhibited broad antitumor activity in xenograft models, both as a monotherapy and with chemotherapy. Methods: Patients (pts) entered escalating dose cohorts of AMG 479 (from 1 to 20 mg/kg administered intravenously [IV] every two weeks [Q2W]). Study objectives were to determine safety, maximum tolerated dose (MTD), pharmacokinetic (PK) parameters, pharmacodynamic (PD) parameters of tumor glucose metabolism (FDG PET/CT), human anti- AMG 479 antibody formation, IGF-1R occupancy in neutrophils, and tumor response (CT RECIST, and PET/CT criteria). Results: Sixteen pts with advanced malignancies were treated with doses from 1 to 20 mg/kg. The median number of cycles was 3 (range 1 to 16). Grade 3 thrombocytopenia was considered dose limiting in 1 pt at 20 mg/kg. Other grade 3/4 non-hematologic toxicities were observed in 2 pts; no hyperglycemia greater than grade 2 was observed. Anti-AMG 479 antibodies, but not neutralizing antibodies, were detected in 1 pt. One pt had an infusion reaction (grade 2 chills/rigors resolving in 15 minutes) but could be retreated following premedication. AMG 479 exhibited dose-linear PK in the dose range from 1 to 20 mg/kg, reaching steady state after 3 doses; mean terminal t1/2 ranged from 7 to 11 days; mean serum clearance ranged from 9 to 14 mL/day/kg; Css exceeded IC90 measured in preclinical models. PD results indicated a trend to dose-proportional occupancy of IGF-1R in neutrophils and increased levels of serum IGF-1 and IGF-BP3 (40% and 20% on day 3, respectively). By CT RECIST criteria, 1 pt with a neuroendocrine tumor had a confirmed partial response and 5 pts had durable stable disease. By FDG-PET/CT criteria, 1 pt with breast cancer had a mixed response. Conclusions: AMG 479 appears to be well tolerated at doses up to 20 mg/kg IV Q2W; dose escalation is complete. AMG 479 administration resulted in PK values adequate for activity in preclinical models, saturable binding of IGF-1R in neutrophils, and preliminary anti-tumor activity. [Table: see text]
Clinical and immunologic effects of a HER2/neu (E75) peptide vaccine booster in previously vaccinated breast cancer patients
Authors: Holmes J. P. , Amin A. , Storrer C. E. , Smith A. M. , Jama Y. H. , McNeil A. , Craig D. , Ponniah S. , Peoples G. E. 
Published: March 2020

3014 Background: We are conducting clinical trials of the HER2/neu E75-peptide vaccine in clinically disease-free breast cancer (BCa) patients. Our Phase I/II trials have shown that the E75+GM-CSF vaccine is safe and effective in stimulating clonal expansion of E75-specific CD8+ T-cells. Since peptide vaccines may not lead to long term immunity, we have assessed the need for and response to a vaccine booster for patients after completion of their primary vaccination series. Methods: BCa patients enrolled in our E75 vaccine trials who were >6 months from the completion of their primary vaccination series were offered a single 1000 mcg dose of E75 peptide with 250 mcg of GM-CSF. Patients were monitored for local and systemic toxicity. E75-specific CD8+ T-cells were quantified using the HLA-A2:IgG dimer before and after booster administration. Results: 19 patients have received the vaccine booster. Median time from primary vaccine series was 12 months (range 6–25) and median residual E75-specific immunity was 0.61% (range 0- 3.43%). Significant residual immunity (SRI=CD8+ E75-specific T-cells >0.5%) was seen in 71% of patients <12 months from primary vaccination vs. 33% of patients ≥12 months. Graded local toxicities were as follows: 18/19 (94.7%) grade 1; 1/19 (5.3%) grade 2. Only 6/19 (31.6%) experienced even grade 1 systemic toxicity. Local reactions were more robust in patients receiving the booster <12 months from primary vaccine compared to those ≥12 months (99±2.8 mm vs. 75±1 mm, p=0.01). In patients lacking SRI, 80% showed increased specific immunity post-vaccination. In these patients, the average CD8+ E75-specific T-cells pre-booster vs. post-booster was 0.37±0.03% vs. 1.06 ± 0.14% (p=0.07). Conclusions: The HER2/neu peptide vaccine E75 stimulates specific immunity in disease-free BCa patients. However, only about half of patients show SRI at median follow-up of 12 months. A vaccine booster is safe and highly effective in stimulating E75-specific immunity especially in those patients without SRI. Initial results suggest that the booster should be given within a year of completion of the initial vaccine series. No significant financial relationships to disclose.
VEGF kinoid vaccine, a therapeutic arm against tumor angiogenesis and metastases
Authors: Ritsou E. , Le Buanec H. , Haghighi Rad F. , Larcier P. , Zagury D. , Uzan G. 
Published: March 2020

3018 Background: Vascular endothelial growth factor (VEGF) plays a central role in neoangiogenesis and thus represents an important therapeutic target in antiangiogenic cancer therapy strategies. We have developed an anti-VEGF vaccine VEGF kinoid that elicits high titres of neutralizing anti-VEGF antibodies in mice. In this study we have evaluated the immunogenicity, safety and efficacy of VEGF kinoid in preventing tumor growth and metastases in mice. Methods: The efficacy of VEGF kinoid was evaluated in a model of active immunization (CT26 colon carcicoma lung metastases model) and in two models of passive immunization. On the passive immunization setting two VEGF secreting xenograft tumor models, A673 rhabdomyosarcoma and HT29 colon carcinoma, were used to evaluate the ability of IgGs derived from kinoid immunized mice to inhibit tumor growth in comparison with bevacizumab. Results: Active immunization with autologous VEGF Kinoid (mVEGF kinoid) triggered a strong anti-VEGF antibody but no cellular immune response in mice. The anti-VEGF Abs exhibited high neutralizing capacity as assessed via inhibition of human umbilical vein endothelial cell proliferation in the presence of VEGF and binding to the Flk-1 receptor. In mVEGF kinoid immunized BALB/c mice challenged with syngeneic CT26 colorectal tumor cells the lung metastases were inhibited. In human VEGF (hVEGF) kinoid immunized Balb/c mice neutralizing anti-hVEGF Abs were elicited. Purified IgG from these mice inhibited tumor growth of human A673 rhabdomyosarcoma and HT29 colon carcinoma cells xenografted in Swiss nude and NOD/SCID mice respectively as assessed by T/C% measurements. Tumor cell growth inhibition was similar to that in mice receiving therapeutic doses of bevacizumab. Active immunization against VEGF showed an excellent safety profile in mice and no impairment of would healing processes was observed after surgical interventions in immunized mice. Conclusions: These experiments show that active immunization with VEGF kinoid elicits polyclonal neutralizing anti-VEGF Abs that inhibit metastases and tumor growth in mice. It may thus represent an alternative strategy to safely combat VEGF-dependent neovascularization and metastases occurring in malignant tumors. No significant financial relationships to disclose.
Immunomonitoring results of a pivotal phase II/III study with the trifunctional antibody catumaxomab (anti-EpCAM x anti-CD3) in ovarian cancer patients with malignant ascites
Authors: Jaeger M. J. , Schoberth A. M. , Heiss M. M. , Lahr A. , Lindhofer H. 
Published: March 2020

3020 Background: Malignant ascites is a symptom of late-stage tumor disease and associated with a poor prognosis. The trifunctional antibody catumaxomab specifically binds to EpCAM+ tumor cells and redirects CD3+ T lymphocytes and FcγR I/III+ accessory cells simultaneously to the tumor site. Methods: 129 (85 catumaxomab; 44 control paracentesis) EpCAM-positive ovarian cancer patients with symptomatic malignant ascites were compared in an open-label, multicenter, randomized study for efficacy and tolerability of intraperitoneally given catumaxomab. Various in vivo and in vitro immunological and pharmacodynamic parameters were measured directly from ascites cell preparations. Results: During the course of catumaxomab treatment in the ascites fluid tumor cells dramatically decreased and leukocytes increased. Accordingly, the in vivo effector/target ratio (CD45+/EpCAM+) showed an drastic increase from a baseline of 6:1 to 10,000:1 already after the first infusion (all median). Leukocyte expansion was accompanied by in vivo upregulation of T cell activation marker CD69 on CD4+ and CD8+ T cells in the ascites fluid and an increase of IL-6 in serum at 24 hours after each infusion indicating systemic effects of catumaxomab. In vitro pharmacodynamic studies were carried out with screening samples to further validate the in vivo results. Similarly, the in vitro experiments showed efficient EpCAM+ tumor cell elimination, leukocyte expansion, drastical improvement of the effector/target ratio and activation of T cells. Additionally, a strong upregulation of activating cytokines IL-2 and IFN-γ (TH1 cytokine profile) and proliferation of CD4+, CD8+ T cells and CD11c+ accessory cells were demonstrated in the samples with catumaxomab compared to controls. Conclusions: Intraperitoneal catumaxomab treatment triggers activation and proliferation of different immune cells and leads to elimination of tumor cells within malignant ascites. These data confirm the postulated mode of action of trifunctional catumaxomab in vivo and correlate with clinical efficacy in patients with malignant ascites. [Table: see text]
Safety and efficacy of eculizumab with concomitant erythropoietin therapy in patients with paroxysmal nocturnal hemoglobinuria (PNH)
Authors: Mojcik C. F. , Young N. S. , Luzzatto L. , Socié G. , Hillmen P. , Brodsky R. A. 
Published: March 2020

3032 Background: Erythropoietins (EPO) are commonly used to improve anemia in patients with bone marrow failure syndromes and in patients with chemotherapy-induced anemia. Two recent phase 3 clinical studies have demonstrated significant benefit of the terminal complement inhibitor, eculizumab (Soliris), in a heterogeneous population of patients with the acquired clonal hemolytic and bone marrow failure disorder, PNH (n=140). While previous studies have shown that EPO is associated with only moderate improvements in fatigue in anemic cancer patients (effect size of 0.5), eculizumab has demonstrated large improvements in fatigue in PNH patients (effect size of 1.1). Methods: To investigate whether eculizumab provides further benefit to PNH patients receiving EPO, efficacy parameters were examined in the EPO subpopulation (n=8). Results: Intravascular hemolysis, as assessed by plasma levels of lactate dehydrogenase (LDH) area under the curve, was reduced 268,271 U/L x day to near normal levels in EPO-treated patients during 26 weeks of eculizumab therapy (p=0.008, signed rank test). Anemia was improved as packed RBC transfusion requirements were substantially reduced with eculizumab in EPO patients from a median of 7.5 units per patient in the 6 months before treatment to 1 unit per patient during eculizumab treatment (p=0.031, signed rank test). Despite pre-existing EPO and transfusion support, eculizumab treatment markedly improved fatigue with a 7.3 point increase over baseline using the FACIT-fatigue instrument (p=0.016, signed rank test; a 3 or more point increase in this instrument has been shown to be clinically meaningful). Eculizumab was well tolerated when administered to PNH patients treated with concomitant EPO with adverse events similar to the overall population. The significant clinical improvements in hematologic and quality of life outcomes with eculizumab treatment in PNH patients receiving concomitant EPO were similar to the clinical improvements demonstrated in the overall PNH patient population. Conclusions: These analyses show that eculizumab treatment provides important clinical benefit when administered to PNH patients receiving EPO support for bone marrow failure. No significant financial relationships to disclose.
A phase II study of the anti-CTLA4 monoclonal antibody (mAb), CP-675,206, in patients with refractory metastatic adenocarcinoma of the colon or rectum
Authors: Chung K. Y. , Gore I. , Fong L. , Venook A. , Dorazio P. , Healey D. , Pavlov D. , Saltz L. B. 
Published: March 2020

3035 Background: The antitumor activity of antibodies to cytotoxic T lymphocyte-associated antigen 4 (CTLA4) has been demonstrated in a variety of murine tumor models, including rejection of established tumors and secondary exposure to tumor cells. This suggests that blockade of the inhibitory effects of CTLA4 can promote effective antitumor immune responses. CP-675,206 has also been shown to induce durable tumor responses in patients (pts) with metastatic melanoma in phase 1 and phase 2 clinical studies. The purpose of this study was to assess safety and efficacy of CTLA4 blockade with the fully human mAb CP-675,206 as single-agent therapy in pts with relapsed/ refractory colorectal cancer. Methods: A single-arm, multicenter, phase II trial of CP-675,206 was conducted in pts with measurable adenocarcinoma of the colon or rectum failing standard treatments and with an ECOG performance status of 0 or 1. Patients received 15 mg/kg Q90 days via IV infusion until disease progression. The primary objective was response rate by RECIST criteria. Secondary objectives included safety, duration of response, progression-free survival, and overall survival. Results: A total of 47 pts who received a median of 4 previous therapies (range, 1 to 9) were treated, and 46 experienced disease progression or death because of disease before reaching the planned second dose at 3 months. Grade 3 or 4 adverse events attributed to study drug were limited to diarrhea (n = 3, 6.4%) and idiopathic thrombocytopenia purpura (n = 1, 2.1%). Four pts (8.5%) had grade 2 diarrhea. Four pts received steroids and 2 received infliximab. One patient was removed for toxicity (diarrhea in the setting of what appeared to be treatment-related ulcerative colitis that was responsive to steroids). One patient (2%; 95% CI = 0%, 11%) had a stable ovarian mass and a substantial regression in an adrenal mass. This patient is continuing on study and has received a second dose. Conclusions: In heavily pretreated pts with colorectal cancer and good performance status, CP- 675,206 was tolerable. However, in this setting, CP-675,206 at 15 mg/kg did not demonstrate substantial single-agent activity. No significant financial relationships to disclose.
Lumiliximab (anti-CD23 antibody) mediates apoptosis and antitumor activity in chronic lymphocytic leukemia (CLL) cells and CD23+ lymphoma cell lines
Authors: Pathan N. , Byrd J. , Hariharan K. , Chu P. , Molina A. 
Published: March 2020

3039 Background: Given the success of treating CLL with antibody therapies, interest in those directed at alternative B-cell antigens remains high. Lumiliximab is a chimeric macaque and human anti-CD23 monoclonal antibody whose antigen is expressed on almost all CLL cells. Methods: We examined lumiliximab’s ability to mediate direct apoptosis, antibody-dependent cellular cytotoxicity (ADCC), and complement-dependent cytotoxicity (CDC) against primary CLL cells and CD23+ B-cell lines. Apoptosis was measured with a flow-cytometry based assay for active caspase-3. ADCC was determined by 51Cr-release assay. CDC assays were performed in the presence of 30% autologous plasma from patients and quantified by propidium iodide staining. Western blotting analysis was used to monitor protein expression before and after treatment with lumiliximab. The CD23+ human lymphoma SKW6.4 cell line was used for in vivo evaluation of lumiliximab in a disseminated human lymphoma model. Results: Lumiliximab mediates apoptosis, ADCC, and CDC in CD23+ B-cell lines. However, in primary CLL cells, the primary mechanism of cell killing appears to be mediated via apoptosis. Apoptosis induced by lumiliximab occurs mainly through the intrinsic pathway used by other CLL therapies. Lumiliximab decreased expression of Bcl-2 and XIAP and inhibited Akt activation in CLL cells. Lumiliximab when combined in vitro or in vivo with rituximab or fludarabine effectively mediates synergistic cytotoxicity against primary CLL cells and CD23+ B-cell lines. Significant antitumor activity was also observed with lumiliximab vs a control antibody in a SCID mouse model of human B-cell lymphoma (P <.01). More importantly, lumiliximab + rituximab or lumiliximab + fludarabine results in prolonged survival vs lumiliximab, rituximab, or fludarabine single-agent treatment. Conclusions: These results indicate that lumiliximab induces apoptosis by activating caspases and downregulating antiapoptotic proteins, and suggest that in combination with rituximab or chemotherapy, lumiliximab synergistically enhances antitumor activity in CLL or other B-cell malignancies in which this antigen is overexpressed. No significant financial relationships to disclose.
Construction and targeting of a 5F11-scFv-methioninase fusion protein for antibody-directed enzyme pro-drug therapy (ADEPT) against neuroblastoma
Authors: Hu J. , Guo H. , Xu H. , Cheung N. V. 
Published: March 2020

3043 Background: Recombinant methioninase (METase) depletes methionine and inhibits tumor growth in preclinical models. 5F11 single-chain variable fragment (scFv) can target fusion proteins (e.g. streptavidin (SA), J. Nucl. Med., 45:867, 2004) preferentially to GD2- positive human neuroblastoma (NB). METase targeted to tumors may release methylselenol from the prodrug selenomethionine for tumor therapy. Methods: 5F11-scFv gene fused upstream of METase in pKK-223–3 to form 5F11-scFv-METase. Fusion protein produced in E. coli and purified by chromatography and endotoxin removal retained enzyme activity. Binding of 5F11-scFv-METase to tumor cells was assayed by indirect immunofluorescence and binding kinetics to GD2 analyzed by surface plasmon resonance. Cytotoxicity against human NB cell lines LAN-1, NMB-7 and SK-N-ER was tested using proliferation inhibition and apoptosis assays. Targeting to NB xenografts was studied by biodistribution using 125I-anti-idiotype 1G8 as the secondary tracking antibody. Results: 5F11-scFv-METase was purified to 84% and 94.1% homogeneity by SDS-PAGE and HPLC, respectively. Enzyme activity was 3.6 units/mg protein. Its avidity (KD=1.72×10-7M) as a dimer compared favorably with the monomeric 5F11-scFv (KD=1.07×10- 7M) and tetrameric 5F11-scFv-SA (KD=2.62×10-9M). Immunofluorescent staining of 5F11-scFv-METase was comparable to 5F11-scFv-SA for LAN-1 and NMB-7. In the presence of 20 μM selenomethionine, IC50 of 5F11-scFv-METase was 0.03, 0.02 and 0.02 units/ml for LAN-1, NMB-7 and SK-N-ER, respectively. When treated with 0.3 units/ml of 5F11-scFv-METase and 20 μM selenomethionine, apoptosis was induced in SK-N-ER by 8 hours, peaking at 24 hours. In biodistribution studies, tumor uptake in LAN-1 xenograft averaged 4.07±0.6% injected dose per gram at 48 hours. Conclusions: 5F11-scFv-METase fusion protein retains enzyme activity and immunoreactivity. It targets to tumors in vivo and activates the pro-drug selenomethionine to effect tumor cytotoxicity. Its potential for tumor-selective methionine depletion as well as in ADEPT applications deserves further studies. No significant financial relationships to disclose.