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Ref Type Journal Article
PMID (29559563)
Authors Hyman DM, Rizvi N, Natale R, Armstrong DK, Birrer M, Recht L, Dotan E, Makker V, Kaley T, Kuruvilla D, Gribbin M, McDevitt J, Lai DW, Dar M
Title Phase I Study of MEDI3617, a Selective Angiopoietin-2 Inhibitor Alone and Combined with Carboplatin/Paclitaxel, Paclitaxel, or Bevacizumab for Advanced Solid Tumors.
Journal Clinical cancer research : an official journal of the American Association for Cancer Research
Vol 24
Issue 12
Date 2018 06 15
URL
Abstract Text Purpose: This first-in-human study aimed to determine the MTD and safety of MEDI3617, a selective anti-angiopoietin-2 (Ang2) mAb, alone and combined with bevacizumab or cytotoxic chemotherapy.Patients and Methods: This phase I/Ib, multicenter, open-label, dose-escalation and dose-expansion study evaluated patients with advanced solid tumors. Patients received intravenous MEDI3617 as monotherapy [5-1,500 mg every 3 weeks (Q3W)] or with bevacizumab every 2 weeks (Q2W) or Q3W, weekly paclitaxel, or carboplatin plus paclitaxel Q3W. Dose expansions included a monotherapy cohort in platinum-resistant ovarian cancer and a bevacizumab combination cohort in bevacizumab-refractory malignant glioma. Safety/tolerability, pharmacokinetics, pharmacodynamics, and clinical activity were assessed.Results: We enrolled 116 patients. No formal MTD was identified (monotherapy or combination therapy). MEDI3617 demonstrated linear pharmacokinetics and maximal accumulation of peripheral Ang2 binding at doses above 300 mg Q3W. MEDI3617 monotherapy safety profile was acceptable, except in advanced ovarian cancer [prolonged grade 3 edema-associated adverse events (AE) occurred]. Otherwise, MEDI3617 combined with chemotherapy or bevacizumab was well tolerated. The AE profiles of MEDI3617 and bevacizumab were largely non-overlapping. Overall response rates in ovarian cancer and glioma monotherapy dose-expansion arms were 6% and 0%, respectively.Conclusions: Recommended MEDI3617 monotherapy dosage is 1,500 mg Q3W or 1,000 mg Q2W, except in ovarian cancer. Although peripheral edema has occurred with other Ang2 inhibitors, the severity and duration seen here in ovarian cancer potentially identifies a new, clinically significant safety signal for this class of agents. On the basis of limited clinical activity, MEDI3617 development was discontinued. Clin Cancer Res; 24(12); 2749-57. ©2018 AACR.

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Molecular Profile Treatment Approach
Gene Name Source Synonyms Protein Domains Gene Description Gene Role
Therapy Name Drugs Efficacy Evidence Clinical Trials
Drug Name Trade Name Synonyms Drug Classes Drug Description
MEDI3617 MEDI3617 is an human monoclonal antibody that prevents the binding of angiopoietin 2 to the Tie2 receptor in vitro, and inhibits angiogenesis and tumor growth in vivo (PMID: 22327175, PMID: 29559563).
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 ovarian cancer not applicable MEDI3617 Phase I Actionable In a Phase I trial, MEDI3617 monotherapy resulted in objective response in 6% (1/17) and stable disease in 30% (5/17) of patients with ovarian cancer, with a median progression-free survival of 1.4 months (PMID: 29559563; NCT01248949). 29559563
Unknown unknown Advanced Solid Tumor not applicable Bevacizumab + MEDI3617 Phase I Actionable In a Phase I trial, MEDI3617 in combination with Avastin (bevacizumab) resulted in objective response (OS) in 7% (2/27) and stable disease (SD) in 37% (10/27) of patients with advanced solid tumors, with a median progression-free survival (mPFS) of 2.0 months in the Q2W (treatment every 2 weeks) arm, and OS in 6% (1/16), SD in 69% (11/16) of patients with a mPFS of 11.4 months in the Q3W arm (PMID: 29559563; NCT01248949). 29559563
Unknown unknown Advanced Solid Tumor not applicable MEDI3617 Phase I Actionable In a Phase I trial, MEDI3617 monotherapy resulted in no objective response (0/25) and stable disease in 52% (13/25) of patients with advanced solid tumors, with a median progression-free survival of 1.4 months (PMID: 29559563; NCT01248949). 29559563
Unknown unknown malignant glioma not applicable Bevacizumab + MEDI3617 Phase I Actionable In a Phase I trial, MEDI3617 in combination with Avastin (bevacizumab) resulted in no objective response (0/11) and stable disease in 18% (2/11) of patients with recurrent malignant glioma, with a median progression-free survival of 1.4 months (PMID: 29559563; NCT01248949). 29559563
Unknown unknown Advanced Solid Tumor not applicable Carboplatin + MEDI3617 + Paclitaxel Phase I Actionable In a Phase I trial, MEDI3617 in combination with Paraplatin (carboplatin) and Taxol (paclitaxel) resulted in no objective response (0/7) and stable disease in 43% (3/7) of patients with advanced solid tumors (PMID: 29559563; NCT01248949). 29559563
Unknown unknown Advanced Solid Tumor not applicable MEDI3617 + Paclitaxel Phase I Actionable In a Phase I trial, MEDI3617 in combination with Taxol (paclitaxel) resulted in objective response in 15% (2/13) and stable disease in 31% (4/13) of patients with advanced solid tumors, with a median progression-free survival of 3.5 months (PMID: 29559563; NCT01248949). 29559563