@article{b7f7552952cc41cdaee3249adb5290a2,
title = "Demcizumab combined with paclitaxel for platinum-resistant ovarian, primary peritoneal, and fallopian tube cancer: The SIERRA open-label phase Ib trial",
abstract = "Objectives: To evaluate the safety and preliminary efficacy of demcizumab (DLL4 targeted IgG2 humanized monoclonal antibody; potent inhibitor of the Notch pathway) in combination with weekly paclitaxel in platinum-resistant epithelial ovarian cancer (EOC); and to determine the maximum tolerated dose (MTD) or maximum administered dose (MAD). Methods: We conducted a 3 + 3 dose-escalation trial in patients with recurrent, platinum-resistant EOC with RECIST v. 1.1 measurable disease and ≤4 prior chemotherapy regimens. Two dosing cohorts (2.5 mg/kg and 5 mg/kg) were targeted; however, an intermediate dose level (3.5 mg/kg) was to be evaluated if the 5 mg/kg dose was not tolerable. Demcizumab was administered on days 1 and 15 and paclitaxel, weekly on days 1, 8, and 15 for each of three 28-day cycles: the 3-cycle doublet could be repeated once if safe. Thereafter, paclitaxel was administered until unacceptable toxicity or disease progression. Results: Nineteen patients were enrolled. No dose-limiting toxicities (DLT) were observed; however, the intermediate dose level (3.5 mg/kg) was enrolled and expanded based on emerging safety data from other trials in the demcizumab program. The MTD was not reached. The most common treatment emergent adverse events (TEAE) were diarrhea (68%), fatigue (58%), peripheral edema (53%), and nausea (53%). Pulmonary hypertension, grade 2 (n = 2) and grade 1 (n = 1), was observed. Overall response rate (ORR) was 21% (95% CI: 6–45%); clinical benefit rate (CBR) was 42% (95% CI: 20–66%). Conclusions: Demcizumab in combination with paclitaxel has a manageable toxicity profile and showed activity in patients with heavily pretreated platinum-resistant ovarian cancer.",
keywords = "DLL4, Delta-like ligand 4, Demcizumab, Notch pathway, Ovarian cancer, Paclitaxel, Platinum-resistant ovarian cancer",
author = "Coleman, {Robert L.} and Handley, {Katelyn F.} and Robert Burger and Molin, {Graziela Zibetti Dal} and Robert Stagg and Sood, {Anil K.} and Moore, {Kathleen N.}",
note = "Funding Information: RLC has clinical research funding from Merck, AstraZeneca/Medimmune, Genentech/Roche, Novartis, Clovis Oncology, Abbvie, and Janssen Pharmaceuticals. KNM has received honoraria for advisory board participation for Astra Zeneca/Medimmune, Genentech/Roche, Clovis Oncology, Janssen Pharmaceuticals, Immunogen, Tesaro, OncoMed, VBL Therapeutics, Aravive, Merck, Samumed and Pfizer. KNM discloses research funding from Lilly, Genentech/Roche, Tesaro, PTC Therapeutics. AKS: Consulting (Merck, Kiyatec), shareholder (BioPath), research funding (M-Trap). All other authors have no conflicts of interest to declare. Funding Information: The study was funded in part by OncoMed Pharmaceutical . RLC is supported by CPRIT RP120214 , the Ann Rife Cox Chair in Gynecology, Judy Reis/Albert Pisani , and the MD Ovarian Cancer Research Fund . KFH is supported by a training fellowship from the Gulf Coast Consortia, on the Computational Cancer Biology Training Program (CPRIT Grant No. RP170593 ). AKS: P50 CA217685, American Cancer Society Research Professor Award, and the Frank McGraw Memorial Chair in Cancer Research. Funding Information: The study was funded in part by OncoMed Pharmaceutical. RLC is supported by CPRIT RP120214, the Ann Rife Cox Chair in Gynecology, Judy Reis/Albert Pisani, and the MD Ovarian Cancer Research Fund. KFH is supported by a training fellowship from the Gulf Coast Consortia, on the Computational Cancer Biology Training Program (CPRIT Grant No. RP170593). AKS: P50 CA217685, American Cancer Society Research Professor Award, and the Frank McGraw Memorial Chair in Cancer Research. Publisher Copyright: {\textcopyright} 2020 Elsevier Inc.",
year = "2020",
month = may,
doi = "10.1016/j.ygyno.2020.01.042",
language = "English (US)",
volume = "157",
pages = "386--391",
journal = "Gynecologic oncology",
issn = "0090-8258",
publisher = "Academic Press Inc.",
number = "2",
}