Demcizumab, Paclitaxel Show Activity in Heavily Pretreated Platinum-Resistant Ovarian Cancer
Demcizumab is a DLL4-targeted lgG2 humanized monoclonal antibody and a potent inhibitor of the Notch pathway. The safety of the drug was evaluated in combination with weekly paclitaxel. Researchers also hoped to estimate the maximum tolerated dose or maximum administered dose, and to determine the recommended phase 2 dose. The secondary goal was objective response rate.
The investigators enrolled 19 patients to participate in the 3+3 dose-escalation trial. All of the participants had recurrent, platinum-resistant EOC and had received 4 or fewer prior chemotherapy regimens. Two dosing cohorts were initially targeted, but an intermediate dose level was prescribed if the 5 mg/kg dose was not tolerable. Intravenous demcizumab was administered on days 1 and 15, and paclitaxel was administered weekly on days 1, 8, and 15 for each of the 3 28-day cycles. Following the cycles, paclitaxel was administered until unacceptable toxicity or disease progression was reached.
In the 19 participants, no dose-limiting toxicity was observed, but an intermediate dose level of 3.5 mg/kg was enrolled in 3 patients and expanded to 10 patients based on emerging safety data from other studies in the demcizumab program.
The most common adverse events were diarrhea (68%), fatigue (58%), peripheral edema (53%), and nausea (53%). Grade 3 or higher adverse events included hypertension (26%), abdominal pain (11%), anemia (11%), neutropenia (11%), and urosepsis (11%). Demcizumab-related adverse events include fatigue (42%), hypertension (37%), diarrhea (32%), and headache (32%). Grades 2 and 3 pulmonary hypertension were observed.
No dose-limiting toxicities were recorded, and the maximum tolerated dose was not reached. The overall response rate was 21%, while the clinical benefit rate was 42%. Two of 5 patients who had received prior bevacizumab treatment had an objective response, and 2 others had confirmed stable disease.
The authors noted that ongoing investigations are evaluating the next-generation bispecific VEGF/DLL4 antibody, navicixizumab, in combination with paclitaxel. Finally, the investigators also noted that more research is needed to confirm and better understand the effects of demcizumab.
Handley K, Moore K, Burger R, Molin G, et al. Demcizumab combined with paclitaxel for platinum-resistant ovarian, primary peritoneal, and fallopian tube cancer (EOC): The SIERRA multi-institutional open-label phase Ib trial. Society of Gynecologic Oncology 2020 meeting website; https://sgo.confex.com/sgo/2020/meetingapp.cgi/Paper/14781. Accessed April 8, 2020.