26 research outputs found
A phase II study of dacetuzumab (SGN-40) in patients with relapsed diffuse large B-cell lymphoma (DLBCL) and correlative analyses of patient-specific factors
BACKGROUND: Patients with DLBCL who are ineligible for or have relapsed after aggressive salvage chemotherapy have a poor prognosis. CD40 is expressed on multiple B-cell neoplasms including DLBCL and is a potential target for immunotherapy. Dacetuzumab (SGN-40), a non-blocking, partial agonist, humanized IgG1, anti-CD40 monoclonal antibody, has previously demonstrated anti-lymphoma activity in a phase I study. METHODS: A phase II study was undertaken to evaluate the rate and duration of objective responses and safety of single-agent dacetuzumab in relapsed DLBCL. Forty-six adult patients with relapsed/refractory DLBCL received up to 12 cycles of intravenous dacetuzumab using intrapatient dose-escalation to a target dose of 8 mg/kg/week in an initial 5-week cycle, followed by 4-week cycles of 8 mg/kg/week. Study endpoints included rate and duration of objective responses, safety, survival, pharmacokinetics, immunogenicity, and exploratory correlative studies. RESULTS: Overall response rate was 9% and disease control rate (complete remission + partial remission + stable disease) was 37%. Common non-hematologic adverse events (AEs) included fatigue, headache, chills, fever, and nausea. The most frequent Grade 3–4 non-hematologic AE was deep venous thrombosis (3 patients). Grade 3–4 lymphopenia (41%), neutropenia (13%), or thrombocytopenia (19%) occurred without associated infection or bleeding. Reversible ocular events, including conjunctivitis and ocular hyperemia, occurred in 8 patients (17%). Patient-specific factors, including Fc-gamma-RIIIa polymorphism, did not appear to correlate with antitumor activity. CONCLUSIONS: Single-agent dacetuzumab has modest activity and manageable toxicity in unselected patients with relapsed DLBCL. Combination regimens and robust methods of patient selection may be necessary for further development. TRIAL REGISTRATION: ClinicalTrials.gov identifier NCT00435916
Duration of Dual Antiplatelet Therapy Following Drug-Eluting Stent Implantation in Diabetic and Non-Diabetic Patients: A Systematic Review and Meta-Analysis of Randomized Controlled Trials
Background: Diabetic patients account for an increasing number of patients undergoing percutaneous coronary intervention (PCI). However, diabetes mellitus (DM) is associated with increased residual platelet activity during dual antiplatelet treatment (DAPT) and DM patients have worse clinical outcomes after PCI as compared to non DM
Induction of polyploidization in leukemic cell lines and primary bone marrow by Src kinase inhibitor SU6656
Megakaryocytes (MKs) undergo successive rounds of endomitosis during differentiation, resulting in polyploidy (typically, 16-64N). Previous studies have demonstrated that this occurs through an interruption of normal cell cycle progression during anaphase. However, the molecular mechanism(s) controlling this unique process is undefined. In the present report, we examine the effect of an Src kinase inhibitor, SU6656, on thrombopoietin (TPO)-induced growth and differentiation. Remarkably, when SU6656 (2.5 μM) was added to a megakaryocytic cell line, UT-7/TPO, the cells ceased cell division but continued to accumulate DNA by endomitosis. During this interval, CD41 and CD61 expression on the cell surface increased. Similar effects on polyploidization and MK differentiation were seen with expanded primary MKs, bone marrow from 2 patients with myelodysplastic syndrome, and other cell lines with MK potential. Our data suggest that SU6656 might be useful as a differentiation-inducing agent for MKs and is an important tool for understanding the molecular basis of MK endomitosis
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SGN-40 (Anti-huCD40 mAb) Monotherapy Induces Durable Objective Responses in Patients with Relapsed Aggressive Non-Hodgkin’s Lymphoma: Evidence of Antitumor Activity from a Phase I Study
Abstract CD40 is a member of the TNF receptor family and is widely expressed on B-cell malignancies. SGN-40 is a humanized antibody against CD40 with effector cell function and partial agonistic activity. Based on potent in vitro and in vivo preclinical activity, a multi-institutional, multi-dose phase I study was conducted to test the safety, pharmacokinetic properties, immunogenicity, and antitumor activity of intravenous SGN-40 in patients with relapsed NHL. Patients with multiple histologic subtypes of NHL were enrolled on this study, including diffuse large B-cell (DLBCL; 14), follicular (FCL; 9), mantle cell (MCL; 9), marginal zone (MZL; 2) and small lymphocytic (SLL; 1). After dose-dependent inflammatory symptoms were identified following the first infusion of SGN-40 in a separate phase I study (i.e. cytokine release syndrome, including headache, fever, muscle aches), this study was modified such that patients were treated with a dose-loading schedule: 1 mg/kg of SGN-40 on day 1 and day 4 and subsequent intra-patient dose-escalation during weeks 2–5 to a maximum dose of 3, 4, 6, or 8 mg/kg over four cohorts. Subsequently, a rapid dose-loading schedule was tested in one cohort (40% increase in total SGN-40 administered during cycle 1). Responding patients or those with stable disease were eligible for a second cycle, consisting of four consecutive weekly infusions at the cohort-specific maximum dose of SGN-40. Most adverse events were grade 1 or 2 and included fatigue (31%), headache (26%), chills (17%), pyrexia (17%), elevated hepatic transaminases (11%), and hypotension (11%). Transient drug-related grade 3 adverse events included conjunctivitis and unilateral loss of visual acuity, anemia, and elevated hepatic transaminases, each in a single patient. There was no difference in the incidence or severity of adverse events at higher doses of SGN-40 nor was there a difference in the safety profiles of the gradual vs. rapid dose-loading schedules. Ten of 35 enrolled patients received a second cycle of treatment without any evidence of cumulative toxicity. No immune responses against SGN-40 have been detected among 16 NHL patients tested to date. Preliminary pharmacokinetic parameters are similar to those seen in preclinical toxicity studies. Durable objective responses have been observed in heavily pre-treated patients. Eight patients with DLBCL completed cycle 1 and received a maximum dose of at least 3 mg/kg SGN-40 with an objective response rate of 37.5% (i.e. 1 CR and 2 PR) and 2 SD. Additional objective responses were seen in one patient with MCL (CR) and one patient with MZL (PR). The median duration of response for these 5 patients has not yet been reached (range 8–37 weeks). Analyses are ongoing to evaluate the role of CD40 expression levels and the relationship of FcγR polymorphisms to response. In conclusion, SGN-40 has favorable safety data and encouraging antitumor activity. A phase II study of single-agent SGN-40 in patients with relapsed DLBCL is planned
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Phase I Study of the Humanized Anti-CD40 Monoclonal Antibody Dacetuzumab in Refractory or Recurrent Non-Hodgkin's Lymphoma
PurposeTo evaluate the safety, maximum-tolerated dose (MTD), pharmacokinetics, and antitumor activity of dacetuzumab in patients with refractory or recurrent B-cell non-Hodgkin's lymphoma (NHL).Patients and MethodsIn this open-label, dose-escalation phase I study, dacetuzumab was administered to six cohorts of adult patients. In the first cohort, patients received 2 mg/kg weekly for 4 weeks; in all other cohorts, an intrapatient dose-escalation schedule was used with increasing doses up to a maximum of 8 mg/kg. Patients with clinical benefit after one cycle of dacetuzumab were eligible for a second cycle.ResultsIn the 50 patients who received dacetuzumab, no dose dependence of adverse events (AEs) was observed. The most common AEs in ≥ 20% of patients were fatigue, pyrexia, and headache; most were grade 1 or 2. Noninfectious inflammatory eye disorders occurred in 12% of patients. AEs grade ≥ 3 occurred in 30% of patients and included disease progression, anemia, pleural effusion, and thrombocytopenia. Most laboratory abnormalities were grade 1 or 2; transient elevated hepatic aminotransferases occurred in 52% of patients. Two patients experienced dose-limiting toxicity: grade 3 conjunctivitis and transient vision loss in cohort (1), and grade 3 ALT elevation in cohort IV. The MTD of dacetuzumab was not established at the dose levels tested. Six objective responses were reported (one complete response, five partial responses). Tumor size decreased in approximately one third of patients.ConclusionDacetuzumab monotherapy was well tolerated in patients with NHL in doses up to 8 mg/kg/wk. Preliminary response data are encouraging and support additional studies of dacetuzumab in this patient population