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|Ref Type||Journal Article|
|Authors||Smith DC, Eisenberg PD, Manikhas G, Chugh R, Gubens MA, Stagg RJ, Kapoun AM, Xu L, Dupont J, Sikic B|
|Title||A phase I dose escalation and expansion study of the anticancer stem cell agent demcizumab (anti-DLL4) in patients with previously treated solid tumors.|
|Journal||Clinical cancer research : an official journal of the American Association for Cancer Research|
|Date||2014 Dec 15|
|Abstract Text||This phase I trial evaluated the safety, pharmacokinetics, and pharmacodynamics of demcizumab (OMP-21M18), a humanized IgG2 mAb targeting the Notch ligand DLL4 in adult patients with advanced malignancies.Standard 3+3 design, with demcizumab 0.5, 1, 2.5, or 5 mg/kg weekly or 2.5, 5, or 10 mg/kg every other week, with an expansion cohort at 10 mg/kg every other week. Dose-limiting toxicities (DLT) were assessed during the first 28 days.Fifty-five patients received demcizumab (15 weekly, 18 every other week, 21 expansion cohort, 1 loading dose). No more than one DLT was seen at any dose level. The MTD was not reached for either schedule. Treatment-related adverse events occurring in >10% of patients were hypertension or blood pressure increased (47%), fatigue (31%), anemia (22%), headache (20%), nausea (13%), hypoalbuminemia (11%), dizziness (11%), and dyspnea (11%). One patient dosed at 2.5 mg/kg developed reversible right-sided heart failure after 63 days on treatment and 4 dosed at 10 mg/kg developed congestive heart failure after ≥98 days on treatment. Five patients were hospitalized with bleeding episodes (2 episodes of tumor-associated bleeding). Sixteen of 25 (64%) evaluable patients at 10 mg/kg had evidence of stabilization of disease or response.Demcizumab was generally well tolerated at doses ≤5 mg weekly with disease stabilization and decreases in tumor size demonstrating antitumor activity. Hypertension was the most common adverse event that was clearly related to treatment. Prolonged administration was associated with an increased risk of congestive heart failure.|
|Molecular Profile||Treatment Approach|
|Gene Name||Source||Synonyms||Protein Domains||Gene Description||Gene Role|
|Drug Name||Trade Name||Synonyms||Drug Classes||Drug Description|
|Demcizumab||OMP-21M18|anti-delta-like 4 monoclonal antibody OMP-21M18||DLL4 Antibody 6||Demcizumab (OMP-21M18) is a monoclonal antibody that binds DLL4 and prevents its interaction with Notch receptors, thereby inhibiting pathway activation and tumor growth (PMID: 19664991, PMID: 25324140, PMID: 32037195).|
|Gene||Variant||Impact||Protein Effect||Variant Description||Associated with drug Resistance|
|Molecular Profile||Indication/Tumor Type||Response Type||Therapy Name||Approval Status||Evidence Type||Efficacy Evidence||References|
|Unknown unknown||Advanced Solid Tumor||not applicable||Demcizumab||Phase I||Actionable||In a Phase I trial, treatment with Demcizumab (OMP-21M18) demonstrated safety and preliminary efficacy in patients with advanced solid tumors (PMID: 25324140).||25324140|
|Unknown unknown||colorectal cancer||not applicable||Demcizumab||Phase I||Actionable||In a Phase I trial, treatment with Demcizumab (OMP-21M18) resulted in downregulation of Notch target genes and demonstrated preliminary efficacy in patients with advanced solid tumors, with reductions in tumor size in patients with several tumor types, including colorectal cancer (PMID: 25324140).||25324140|