First-in-Human Phase I Study of Single-agent Vanucizumab, A First-in-Class Bispecific Anti-Angiopoietin-2/Anti-VEGF-A Antibody, in Adult Patients with Advanced Solid Tumors

Abstract

Vanucizumab is an investigational antiangiogenic, first-in-class, bispecific mAb targeting VEGF-A and angiopoietin-2 (Ang-2). This first-in-human study evaluated the safety, pharmacokinetics, pharmacodynamics, and antitumor activity of vanucizumab in adults with advanced solid tumors refractory to standard therapies. Patients received escalating biweekly (3-30 mg/kg) or weekly (10-30 mg/kg) intravenous doses guided by a Bayesian logistic regression model with overdose control. Forty-two patients were treated. One dose-limiting toxicity, a fatal pulmonary hemorrhage from a large centrally located mediastinal mass judged possibly related to vanucizumab, occurred with the 19 mg/kg biweekly dose. Arterial hypertension (59.5%), asthenia (42.9%), and headache (31%) were the most common toxicities. Seventeen (41%) patients experienced treatment-related grade ≥3 toxicities. Toxicity was generally higher with weekly than biweekly dosing. A MTD of vanucizumab was not reached in either schedule. Pharmacokinetics were dose-linear with an elimination half-life of 6-9 days. All patients had reduced plasma levels of free VEGF-A and Ang-2; most had reductions in K (measured by dynamic contrast-enhanced MRI). Two patients (renal cell and colon cancer) treated with 30 mg/kg achieved confirmed partial responses. Ten patients were without disease progression for ≥6 months. A flat-fixed 2,000 mg biweekly dose (phamacokinetically equivalent to 30 mg/kg biweekly) was recommended for further investigation. Biweekly vanucizumab had an acceptable safety and tolerability profile consistent with single-agent use of selective inhibitors of the VEGF-A and Ang/Tie2 pathway. Vanucizumab modulated its angiogenic targets, impacted tumor vascularity, and demonstrated encouraging antitumor activity in this heterogeneous population. .

The McCAVE Trial: Vanucizumab plus mFOLFOX-6 Versus Bevacizumab plus mFOLFOX-6 in Patients with Previously Untreated Metastatic Colorectal Carcinoma (mCRC)

“…These observations suggested that Ang‐2 suppression may be a predictor of benefit from an anti−VEGF‐A containing therapy but also underscored the potential value of simultaneous targeting of VEGF‐A and Ang‐2 . The McCAVE trial demonstrates that vanucizumab/mFOLFOX‐6 treatment was associated with modulation of the primary target Ang‐2 and systemic exposures of vanucizumab/mFOLFOX‐6, consistent with those previously reported . However, our results found no improvement in either PFS or ORR for vanucizumab compared with bevacizumab in patients with mCRC treated in combination with mFOLFOX‐6.…”

“…As in the previous study of single‐agent vanucizumab , free Ang‐2 levels in plasma rapidly decreased after vanucizumab dosing, whereas levels of total (free plus drug‐bound) Ang‐2 increased (Fig. ).…”

“…Vanucizumab showed potent tumor growth inhibition in a panel of human tumor xenograft models with superior antitumor activity in larger tumors compared with the monospecific antibodies, supporting the notion that larger tumors exhibit different vessel types that do not all respond equally to anti–VEGF‐A therapy . The observed clinical safety profile of single‐agent vanucizumab was consistent with that reported for selective inhibitors of the VEGF‐A and angiopoietin‐Tie2 signaling pathway and showed encouraging antitumor activity in a heterogeneous patient population . The purpose of the current study, also known as BP29262 or the McCAVE trial, was to determine if concurrent target inhibition of the VEGF‐A and Ang‐2 axis by adding vanucizumab to standard chemotherapy can improve the treatment outcome versus bevacizumab plus chemotherapy in treatment‐naïve patients with mCRC.…”

“…Systemic exposure of vanucizumab was assessed by noncompartmental and population pharmacokinetic (PK) analysis and was consistent with that seen after single‐agent administration of vanucizumab (data not shown). Likewise, PK parameters for oxaliplatin (total and free) and 5‐FU were also similar to the ones previously reported .…”

Hydrogels based on chitosan in tissue regeneration: How do they work? A mini review

“…First, the controlled release file may reduce the risk factors of biological additives. For instance, many basic medical studies indicated that the overexpression of VEGF was probably a significant reason for oncogenesis, dermatomyositis, and pterygium . Therefore, a slow, low‐level, and steady release rate of growth factors can prevent these side effects.…”