A phase Ib study to assess the safety of lexatumumab, a human monoclonal antibody that activates TRAIL-R2, in combination with gemcitabine, pemetrexed, doxorubicin or FOLFIRI

2007 ◽  
Vol 25 (18_suppl) ◽  
pp. 14006-14006 ◽  
Author(s):  
B. I. Sikic ◽  
H. A. Wakelee ◽  
M. von Mehren ◽  
N. Lewis ◽  
A. H. Calvert ◽  
...  
Keyword(s):  
Monoclonal Antibody ◽  
Tumor Necrosis Factor ◽  
Tumor Necrosis ◽  
Human Monoclonal Antibody ◽  
Single Agent ◽  
Tumor Necrosis Factor Receptor ◽  
Chemotherapeutic Agents ◽  
Extrinsic Pathway ◽  
Wide Range ◽  
Necrosis Factor

14006 Background: Lexatumumab (HGS-ETR2) is a fully-human agonistic monoclonal antibody that targets and activates the Tumor Necrosis Factor-Related Apoptosis-Inducing Ligand Receptor 2 (TRAIL-R2). TRAIL-R2 is a member of the Tumor Necrosis Factor Receptor (TNFR) superfamily that, when activated, induces apoptosis via the extrinsic pathway. Lexatumumab shows promising anti-tumor activity in preclinical models, particularly in combination with chemotherapeutic agents. Single-agent lexatumumab was well-tolerated in phase I trials. This is the first study of the safety of a TRAIL-R2 agonist in combination with chemotherapy. Methods: Patients for whom gemcitabine, pemetrexed, doxorubicin or FOLFIRI was considered an appropriate treatment received one of the full-dose chemotherapy regimens plus lexatumumab every 2 weeks (for gemcitabine and FOLFIRI) or 3 weeks (for pemetrexed and doxorubicin). Four to 6 patients were treated with 5 mg/kg lexatumumab in each chemotherapy cohort prior to dose escalation to 10 mg/kg. Results: To date, 41 patients with a wide range of cancer types have received 164 courses of lexatumumab over the 2 dose levels. The majority (33/41) received at least 2 courses (range 1 to 19). Lexatumumab was well-tolerated; no dose reductions of lexatumumab were required. Severe adverse events considered at least possibly related to lexatumumab included anemia, fatigue and dehydration. Tumor shrinkage has been observed, including confirmed partial responses (PRs) in the FOLFIRI and doxorubicin arms. Eight patients continue on study. Conclusions: Lexatumumab can be safely administered in combination with a wide range of chemotherapeutic agents. Evaluation of the efficacy of lexatumumab in combination with chemotherapy in Phase 2 trials is warranted. [Table: see text]

scholarly journals Characterization of golimumab, a human monoclonal antibody specific for human tumor necrosis factor α

mAbs ◽  
2010 ◽  
Vol 2 (4) ◽  
pp. 428-439 ◽  
Author(s):  
David J. Shealy ◽  
Ann Cai ◽  
Kim Staquet ◽  
Audrey Baker ◽  
Eilyn R. Lacy ◽  
...  
Keyword(s):  
Monoclonal Antibody ◽  
Tumor Necrosis Factor ◽  
Tumor Necrosis ◽  
Tumor Necrosis Factor Α ◽  
Human Monoclonal Antibody ◽  
Human Tumor ◽  
Human Tumor Necrosis Factor ◽  
Factor Α ◽  
Necrosis Factor

scholarly journals A Critical Role of the p75 Tumor Necrosis Factor Receptor (p75TNF-R) in Organ Inflammation Independent of  TNF, Lymphotoxin α, or the p55TNF-R

1998 ◽  
Vol 188 (7) ◽  
pp. 1343-1352 ◽  
Author(s):  
Eleni Douni ◽  
George Kollias
Keyword(s):  
Tumor Necrosis Factor ◽  
Tumor Necrosis ◽  
Critical Role ◽  
Tumor Necrosis Factor Receptor ◽  
Peripheral Blood Mononuclear ◽  
Enhanced Production ◽  
Wide Range ◽  
Lymphotoxin Α ◽  
Necrosis Factor

Despite overwhelming evidence that enhanced production of the p75 tumor necrosis factor receptor (p75TNF-R) accompanies development of specific human inflammatory pathologies such as multi-organ failure during sepsis, inflammatory liver disease, pancreatitis, respiratory distress syndrome, or AIDS, the function of this receptor remains poorly defined in vivo. We show here that at levels relevant to human disease, production of the human p75TNF-R in transgenic mice results in a severe inflammatory syndrome involving mainly the pancreas, liver, kidney, and lung, and characterized by constitutively increased NF-κB activity in the peripheral blood mononuclear cell compartment. This process is shown to evolve independently of the presence of TNF, lymphotoxin α, or the p55TNF-R, although coexpression of a human TNF transgene accelerated pathology. These results establish an independent role for enhanced p75TNF-R production in the pathogenesis of inflammatory disease and implicate the direct involvement of this receptor in a wide range of human inflammatory pathologies.

Phase I Pharmacokinetic and Biologic Correlative Study of Mapatumumab, a Fully Human Monoclonal Antibody With Agonist Activity to Tumor Necrosis Factor–Related Apoptosis-Inducing Ligand Receptor-1

2007 ◽  
Vol 25 (11) ◽  
pp. 1390-1396 ◽  
Author(s):  
Anthony W. Tolcher ◽  
Monica Mita ◽  
Neal J. Meropol ◽  
Margaret von Mehren ◽  
Amita Patnaik ◽  
...  
Keyword(s):  
Monoclonal Antibody ◽  
Single Dose ◽  
Tumor Necrosis Factor ◽  
Tumor Necrosis ◽  
Human Monoclonal Antibody ◽  
Preliminary Evidence ◽  
Hematologic Toxicity ◽  
Broad Array ◽  
Clinically Significant ◽  
Necrosis Factor

PurposeTo assess the safety, pharmacokinetics, and preliminary evidence of antitumor activity of mapatumumab (HGS-ETR1, TRM-1), a fully human agonist monoclonal antibody directed to the tumor necrosis factor–related apoptosis-inducing ligand receptor-1 (TRAIL-R1).Patients and MethodsPatients with advanced solid malignancies were treated with escalating doses of mapatumumab intravenously (IV) administered over 30 to 120 minutes, initially as a single dose and then repetitively. Plasma mapatumumab concentrations were measured and serum was assayed to detect human antimapatumumab antibody formation. Archival tumor specimens were collected to detect the presence of TRAIL-R1 by immunohistochemistry.ResultsForty-nine patients received 158 courses at doses ranging from 0.01 to 10 mg/kg IV. Initially, patients received mapatumumab as a single dose, then every 28 days repetitively, and then 10 mg/kg every 14 days. Mild (grade 1 or 2) fatigue, fever, and myalgia were the most frequently reported nonhematologic adverse events related to mapatumumab, whereas hematologic toxicity was not clinically significant. The mean (± standard deviation) clearance and terminal elimination half-life values for mapatumumab at 10 mg/kg every 14 days were 3.7 mL/d/kg (± 1.5 mL/d/kg) and 18.8 days (± 10.1 days), respectively. TRAIL-R1 was documented in 68% of patients' tumors assayed. Nineteen patients had stable disease, with two lasting 9 months.ConclusionMapatumumab can be administered safely and feasibly at 10 mg/kg IV every 14 days. The absence of severe toxicities and the attainment of plasma mapatumumab concentrations that are active in preclinical models warrant further disease-directed studies of this agent alone and in combination with chemotherapy in a broad array of tumors.

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