Clinical trial experience with CA4P anticancer therapy: focus on efficacy, cardiovascular adverse events, and hypertension management

Abstract

Combretastatin A4-phosphate (CA4P) is a vascular-disrupting agent (VDA) in clinical development for the treatment of ovarian and other cancers. In contrast to antiangiogenic agents, such as bevacizumab, which suppress the development of new tumor vasculature, VDAs target established tumor vasculature. These differing but complementary mechanisms of action are currently being explored in clinical trials combining CA4P and bevacizumab. Clinical experience to date has highlighted an important need to better understand the cardiovascular adverse events of CA4P, both alone and in combination with antiangiogenic agents, which can also be associated with cardiovascular adverse events.An acute but transient increase in blood pressure is often the most clinically relevant toxicity associated with CA4P. Increases in CA4P-related blood pressure typically occur 0.5 to 1 h after initiation of the 10-min infusion, peak by 2 h, and return to baseline 3 to 4 h after the infusion. Post-infusion increases in blood pressure are likely to recur in subsequent treatment cycles; however, the severity does not appear to increase with successive cycles. Other cardiovascular adverse events, such as transient, predominantly grade 1–2 tachycardia, bradycardia, QTc prolongation, and in rare cases myocardial ischemia, have also been observed with CA4P but at markedly lower frequencies than hypertension.The clinical trial experience with CA4P suggests that cardiovascular assessment of patients prior to CA4P treatment and careful management of blood pressure during CA4P treatment can largely mitigate the risk of cardiovascular adverse events. Accordingly, we have developed a blood pressure management algorithm for use in the ongoing phase II/III FOCUS study of the triple combination of CA4P with physician’s choice chemotherapy and bevacizumab.

Phase I and pharmacokinetic study of the vascular‐disrupting agent CKD‐516 (NOV120401) in patients with refractory solid tumors

“…In contrast, oral CKD‐516 was not associated with hypertension, which was the only DLT observed in the intravenous CKD‐516 trial . Notably, oral CKD‐516 demonstrated no significant cardiovascular adverse events that are observed with other VDAs …”

Antitumor Drug Combretastatin-A4 Phosphate Aggravates the Symptoms of Dextran Sulfate Sodium-Induced Ulcerative Colitis in Mice

“…CA4P, a water-soluble prodrug of CA4, is used as a vasculardisrupting agent for the treatment of ovarian, glioma, non-small cell lung cancer (NSCLC), pancreatic neuroendocrine tumors, and etc. (Grisham et al, 2018). CA4P monotherapy is well tolerated, and most adverse events during cancer treatment are mild to moderate in intensity.…”

Anti-tumor efficacy of CKD-516 in combination with radiation in xenograft mouse model of lung squamous cell carcinoma

“…Some preclinical and clinical studies have reported the e cacy and safety pro les of VDAs [12][13][14][15][16]. In theory, radiation therapy is not effective at locally controlling hypoxic areas in tumor tissues.…”