Abstract B78: A Phase Ib study of demcizumab (DEM, anti-DLL4) with gemcitabine (GEM) in patients with first line locally advanced or metastatic pancreatic cancer.

Background: Delta-like ligand 4 (DLL4) is a ligand that activates the Notch pathway which is important for cancer stem cell (CSC) survival. DEM is a humanized IgG 2 anti-DLL4 antibody that has been shown to inhibit tumor growth and decrease CSC frequency in minimally passaged human xenograft models. In addition, inhibition of DLL4 has also been shown in preclinical studies to cause dysfunctional sprouting of new vessels resulting in an antiangiogenic effect. DEM also showed synergistic activity when combined with GEM in human pancreatic tumor-derived xenograft models. Material and Methods: Patients with first line stage III or IV pancreatic cancer received DEM (2.5 every 2 or 4 wks or 5 mg/kg every 4 wks) and GEM 1000 mg/m 2 7 of the 1st 8 wks and then 3 of every 4 wks until disease progression. The primary objective was to determine the maximum tolerated dose of DEM. Other objectives included: safety, efficacy, immunogenicity, pharmacokinetic, and biomarkers of Notch signaling and CSCs. Results: Twenty four patients were enrolled; 8 pts received 2.5 mg/kg every 2 wks, 8 received 2.5 mg/kg every 4 wks and 8 received 5 mg/kg every 4 wks of DEM. The median age was 65.5 yrs. Three (12.5%) and 21 (87.5%) patients had stage III and IV disease, respectively. Seven, 16 and 1 patients were ECOG performance status 0, 1, and 2, respectively. Related adverse events (all grades) in ≥10% of patients included: fatigue (29%), hypertension (29%), vomiting (29%), nausea (25%), thrombocytopenia (21%), decreased appetite (21%), increased B-type natriuretic peptide (BNP) (13%), anemia (13%), peripheral edema (13%), pulmonary hypertension (13%), dizziness (13%) and rash (13%). The hypertension was successfully managed with oral anti-hypertensives. Increased BNP values appear to be an early indicator of the cardiac effects of DEM and mildly elevated values are being used to initiate cardioprotective therapy with an ACE inhibitor or carvedilol. One patient who received 5 mg/kg developed reversible pulmonary hypertension and heart failure on study day 143. As a result, the duration of DEM will be limited to 70 days in subsequent cohorts and paclitaxel protein-bound particles will also be added to the regimen. Four of 16 (25%) evaluable patients had a RECIST partial response and 7 had stable disease. The median progression free survival for the 5 mg/kg cohort was 5.9 months. The pharmacokinetic and immunogenicity samples are being analyzed and these data will be presented. Conclusion: DEM plus GEM was generally well tolerated with fatigue, hypertension and vomiting being the most common drug related adverse events. The duration of demcizumab therapy is being limited to 70 days in subsequent cohorts due to cardiopulmonary toxicity which was observed following more prolonged administration. Encouraging early clinical activity has been observed. Subsequent cohorts will include paclitaxel protein-bound particles. Enrollment is ongoing and updated results will be presented. Citation Information: Mol Cancer Ther 2013;12(11 Suppl):B78. Citation Format: Antonio Cubillo, Michael Jameson, Enrique Grande, Francis Parnis, Peter Grimison, Prasad Cooray, Mark Jeffery, Robert Stagg, Jakob Dupont, Niall Tebbutt. A Phase Ib study of demcizumab (DEM, anti-DLL4) with gemcitabine (GEM) in patients with first line locally advanced or metastatic pancreatic cancer. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2013 Oct 19-23; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2013;12(11 Suppl):Abstract nr B78.