A phase 1 dose-escalation and dose-expansion study to assess the safety and efficacy of CKD-516, a novel vascular disrupting agent, in combination with Irinotecan in patients with previously treated metastatic colorectal cancer.

Introduction The combination of an anti-angiogenic agent with cytotoxic chemotherapy is a standard treatment strategy for metastatic colorectal cancer. CKD-516 is an oral vascular disrupting agent that was preliminarily shown to be safe and efficacious as a monotherapy in refractory solid cancers. We evaluated the recommended phase 2 dose, safety, and preliminary efficacy of CKD-516 in combination with irinotecan in treatment-refractory metastatic colorectal cancer. Methods This phase 1 dose-escalation and dose-expansion study included patients with treatment-refractory metastatic colorectal cancer. CKD-516 tablets were administered for five consecutive days followed by two days off in combination with intravenous irinotecan (120 mg/m2) administered on day one of each treatment cycle every two weeks. A traditional 3 + 3 dose-escalation design was used. Results In total, 16 and 23 patients were enrolled in the dose-escalation and dose-expansion cohorts, respectively. The most common adverse events included diarrhea (79%), nausea (74%), vomiting (67%), and neutropenia (62%). No dose-limiting toxicity occurred, and the recommended phase 2 dose was determined at CKD-516/irinotecan doses of 11/120 mg/m2. No cases of cardiac ischemia, cardiac dysfunction, or thromboembolism were reported. Among the 34 patients with available tumor response assessments, one patient achieved partial response (3%) and 26 patients achieved stable disease (76%). The median progression-free survival and overall survival were 4.1 and 11.6 months, respectively. Conclusion This phase 1 study showed that the combination of oral CKD-516 and irinotecan is safe and tolerable in metastatic, treatment-refractory colorectal patients and showed favorable efficacy outcomes. Further studies to confirm these preliminary findings are warranted. Trial registration number NCT03076957 (Registered at March 10, 2017).

CKD-516 potentiates the anti-cancer activity of docetaxel against epidermal growth factor receptor tyrosine kinase inhibitor-resistant lung cancer.

Lung cancer is the leading cause of cancer death. Although docetaxel has been used as a second- or third-line treatment for non-small cell lung cancer (NSCLC), the objective response rate is less than 10%. Hence, there is a need to improve the clinical efficacy of docetaxel monotherapy; combination therapy should be considered. Here, we show that CKD-516, a vascular disruption agent, can be combined with docetaxel to treat epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitor (TKI)-resistant NSCLC. CKD-516 was orally bioavailable; neither CKD-516 nor docetaxel affected the mean plasma concentration-time profile or pharmacokinetic parameters of the other drug. CKD-516 and docetaxel synergistically inhibited the growth of H1975 (with an L858R/T790M double mutation of EGFR) and A549 (with a KRAS mutation) lung cancer cell lines. In addition, docetaxel plus CKD-516 delayed tumor growth in-and extended the lifespan of-tumor-bearing mice. Thus, combination CKD-516 and docetaxel therapy could be used to treat EGFR-TKI-resistant NSCLC.

Involvement of ER stress and reactive oxygen species generation in anti-cancer effect of CKD-516 for lung cancer.

PURPOSE: CKD-516 (Valecobulin), a vascular-disrupting agent, inhibits microtubule elongation. We evaluated the effect of CKD-516 on lung cancer cells and the underlying molecular mechanisms. METHODS: The effects of S516, an active metabolite of CKD-516, were evaluated in HUVECs and three lung cancer cell lines and by a microtubule polymerization assay. Tubulin cross-linking was used to identify the binding site of S516 on tubulin, and Western blotting was performed to identify the intracellular pathways leading to cell death. Subcutaneous lung cancer xenograft models were used to assess the in vivo effect of CKD-516 on tumor growth. RESULTS: S516 targeted the colchicine binding site on ß-tubulin. In lung cancer cells, S516 increased endoplasmic reticulum (ER) stress and induced reactive oxygen species (ROS) generation by mitochondria and the ER. In addition, CKD-516 monotherapy strongly inhibited the growth of lung cancer xenograft tumors and exerted a synergistic effect with carboplatin. CONCLUSION: The findings suggest that CKD-516 exerts an anticancer effect in company with inducing ER stress and ROS production via microtubule disruption in lung cancer cells. CKD-516 may thus have therapeutic potential for lung cancer.

Enhanced efficacy of radiofrequency ablation for hepatocellular carcinoma using a novel vascular disrupting agent, CKD-516.

BACKGROUND: CKD-516 is a novel vascular disrupting agent that shuts down intratumoral blood flow. We therefore hypothesized that concomitant administration of CKD-516 would enhance the therapeutic efficacy of radiofrequency ablation (RFA) by reducing heat sink effects. We assessed the effects of the combination of CKD-516 and RFA in a rat orthotopic hepatocellular carcinoma (HCC) model. METHODS: Rat HCC cells (N1-S1) were engrafted into the hepatic lobe of Sprague-Dawley (SD) rats. Mice were randomly divided into two groups: RFA-only and CKD-RFA. In the CKD-RFA group, CKD-516 was administered by intraperitoneal injection 2 h before RFA. Ablation zone size was measured on triphenyltetrazolium chloride-stained specimens. Terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) staining was performed to evaluate the area of apoptosis/necrosis in the ablation zone. Immunohistochemistry with anti-CD31 antibody was performed to evaluate the effect of CKD-516 on tumor vessels. RESULTS: Ablation zone size was significantly larger in the CKD-RFA group than in the RFA-only group (243.10 ± 74.39 versus 123.30 ± 28.17 mm2, p < 0.001). On TUNEL staining, the area of apoptosis/necrosis was also significantly larger in the CKD-RFA group than in the RFA-only group (274.44 ± 140.78 versus 143.74 ± 90.13 mm2; p = 0.006). Immunohistochemistry with anti-CD31 antibody revealed patent tumor vessels in the RFA-only group, while collapsed vessels were seen in the CKD-RFA group, indicating a vascular shutdown effect of CKD-516. CONCLUSION: Concomitant administration of CKD-516 during RFA can increase the ablation zone of tumors due to its vascular disrupting effect.

Phase I Study of CKD-516, a Novel Vascular Disrupting Agent, in Patients with Advanced Solid Tumors.

PURPOSE: CKD-516 is a newly developed vascular disrupting agent. This phase I dose-escalation study of CKD-516 was conducted to determine maximum-tolerated dose (MTD), safety, pharmacokinetics, and preliminary antitumor efficacy in patients with advanced solid tumors. MATERIALS AND METHODS: Patients received CKD-516 intravenously on D1 and D8 every 3 weeks, in a standard 3+3 design. Safety was evaluated by National Cancer Institute Common Terminology Criteria for Adverse Events ver. 4.02 and response was assessed by Response Evaluation Criteria in Solid Tumor ver. 1.1. RESULTS: Twenty-three patients were treated with CKD-516 at seven dosing levels: 1 mg/m(2)/day (n=3), 2 mg/m(2)/day (n=3), 3.3 mg/m(2)/day (n=3), 5 mg/m(2)/day (n=3), 7 mg/m(2)/day (n=3), 9 mg/m(2)/day (n=6), and 12 mg/m(2)/day (n=2). Mean age was 54 and 56.5% of patients were male. Two dose-limiting toxicities, which were both grade 3 hypertension, were observed in two patients at 12 mg/m(2)/day. The MTD was determined as 12 mg/m(2)/day. Most common adverse events were gastrointestinal adverse events (diarrhea, 34.8% [30.4% grade 1/2, 13.0% grade 3]; nausea, 21.7% [all grade 1/2]; vomiting, 21.7% [all grade 1/2]), myalgia (17.4%, all grade 1/2), and abdominal pain (21.7% [21.7% grade 1/2, 4.3% grade 3]). The pharmacokinetic study showed the dose-linearity of all dosing levels. Among 23 patients, six patients (26.1%) showed stable disease. Median progression-free survival was 39 days (95% confidence interval, 37 to 41 days). CONCLUSION: This study demonstrates feasibility of CKD-516, novel vascular disrupting agent, in patients with advanced solid tumor. MTD of CKD-516 was defined as 12 mg/m(2)/day on D1 and D8 every 3 weeks.

Early quantification of the therapeutic efficacy of the vascular disrupting agent, CKD-516, using dynamic contrast-enhanced ultrasonography in rabbit VX2 liver tumors.

PURPOSE: To evaluate the usefulness of dynamic contrast-enhanced ultrasonography (DCE-US) in the early quantification of hemodynamic change following administration of the vascular disrupting agent (VDA) CKD-516 using a rabbit VX2 liver tumor model. METHODS: This study was approved by our institutional animal care and use committee. Eight VX2 liver-tumor-bearing rabbits were treated with intravenous CKD-516, and all underwent DCE-US using SonoVue before and again 2, 4, 6, and 24 hours following their treatment. The tumor perfusion parameters were obtained from the time-intensity curve of the DCE-US data. Repeated measures analysis of variance was performed to assess any significant change in tumor perfusion over time. Relative changes in the DCE-US parameters between the baseline and follow-up assessments were correlated with the relative changes in tumor size over the course of seven days using Pearson correlation. RESULTS: CKD-516 treatment resulted in significant changes in the DCE-US parameters, including the peak intensity, total area under the time-intensity curve (AUCtotal), and AUC during wash-out (AUCout) over time (P<0.05). Pairwise comparison tests revealed that the AUCtotal and AUC during wash-in (AUCin) seen on the two-hour follow-up were significantly lower than the baseline values (P<0.05). However, none of early changes in the DCE-US parameters until 24-hour follow-up showed a significant correlation with the relative changes in tumor size during seven days after CKD-516 treatment. CONCLUSION: Our results suggest that a novel VDA (CKD-516) can cause disruption of tumor perfusion as early as two hours after treatment and that the therapeutic effect of CKD-516 treatment can be effectively quantified using DCE-US.

Enhanced efficacy of CKD-516 in combination with doxorubicin: pre-clinical evaluation using a hepatocellular carcinoma xenograft model.

AIM: To evaluate the anticancer efficacy of CKD-516, a novel vascular-disrupting agent, alone and in combination with doxorubicin in the treatment of hepatocellular carcinoma (HCC). MATERIALS AND METHODS: In mice bearing luciferized HCC cells, therapeutic efficacy was assessed for seven days after single administration of CKD-516, doxorubicin, or combination of CKD-516 and doxorubicin. RESULTS: Bioluminescence-imaging (BLI) signals in the CKD-516 group abruptly decreased initially, but recovered at seven days after treatment. BLI signals in the doxorubicin group gradually decreased over the 7-day period. In the combination group, BLI signals were abruptly reduced and remained suppressed for the 7-day period. On histopathological examination, CKD-516-treated tumors showed extensive central necrosis, whereas the peripheral layers remained viable. Doxorubicin-treated tumors showed mild and scattered necrosis. Tumors from the combination group showed more extensive central and peripheral necrosis, with smaller viable peripheral layers than the CKD-516 group. CONCLUSION: Combination therapy can have additive effects for treatment of HCC compared with CKD-516 or doxorubicin monotherapy.