Phase I study of MEDI3617, a selective angiopoietin-2 inhibitor alone and combined with carboplatin/paclitaxel, paclitaxel, or bevacizumab for advanced solid tumors Journal Article


Authors: Hyman, D. M.; Rizvi, N.; Natale, R.; Armstrong, D. K.; Birrer, M.; Recht, L.; Dotan, E.; Makker, V.; Kaley, T.; Kuruvilla, D.; Gribbin, M.; McDevitt, J.; Lai, D. W.; Dar, M.
Article Title: Phase I study of MEDI3617, a selective angiopoietin-2 inhibitor alone and combined with carboplatin/paclitaxel, paclitaxel, or bevacizumab for advanced solid tumors
Abstract: 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. © 2018 American Association for Cancer Research.
Journal Title: Clinical Cancer Research
Volume: 24
Issue: 12
ISSN: 1078-0432
Publisher: American Association for Cancer Research  
Date Published: 2018-06-01
Start Page: 2749
End Page: 2757
Language: English
DOI: 10.1158/1078-0432.ccr-17-1775
PROVIDER: scopus
PUBMED: 29559563
DOI/URL:
Notes: Article -- Export Date: 1 October 2018 -- Source: Scopus
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MSK Authors
  1. Vicky Makker
    73 Makker
  2. Thomas Kaley
    82 Kaley
  3. David Hyman
    181 Hyman