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Dose-response assessment by quantitative MRI in a phase 1 clinical study of the anti-cancer vascular disrupting agent crolibulin.

ABSTRACT: The vascular disrupting agent crolibulin binds to the colchicine binding site and produces anti-vascular and apoptotic effects. In a multisite phase 1 clinical study of crolibulin (NCT00423410), we measured treatment-induced changes in tumor perfusion and water diffusivity (ADC) using dynamic contrast-enhanced MRI (DCE-MRI) and diffusion-weighted MRI (DW-MRI), and computed correlates of crolibulin pharmacokinetics. 11 subjects with advanced solid tumors were imaged by MRI at baseline and 2-3 days post-crolibulin (13-24 mg/m²). ADC maps were computed from DW-MRI. Pre-contrast T₁ maps were computed, co-registered with the DCE-MRI series, and maps of area-under-the-gadolinium-concentration-curve-at-90 s (AUC_90s) and the Extended Tofts Model parameters k^trans, v_e, and v_p were calculated. There was a strong correlation between higher plasma drug [Formula: see text] and a linear combination of (1) reduction in tumor fraction with [Formula: see text] mM s, and, (2) increase in tumor fraction with [Formula: see text]. A higher plasma drug AUC was correlated with a linear combination of (1) increase in tumor fraction with [Formula: see text], and, (2) increase in tumor fraction with [Formula: see text]. These findings are suggestive of cell swelling and decreased tumor perfusion 2-3 days post-treatment with crolibulin. The multivariable linear regression models reported here can inform crolibulin dosing in future clinical studies of crolibulin combined with cytotoxic or immune-oncology agents.

SUBMITTER: Lorza AMA

PROVIDER: S-EPMC7468301 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Quantitative Evaluation of Tumor Early Response to a Vascular-Disrupting Agent with Dynamic PET.

Project description:PurposeThe purpose of this study is to evaluate the early response of tumors to a vascular-disrupting agent (VDA) VEGF121/recombinant toxin gelonin (rGel) using dynamic [(18)F]FPPRGD2 positron emission tomography (PET) and kinetic parameter estimation.ProceduresTwo tumor xenograft models: U87MG (highly vascularized) and A549 (moderately vascularized), were selected, and both were randomized into treatment and control groups. Sixty-minute dynamic PET scans with [(18)F]FPPRGD2 that targets to integrin αvβ3 were performed at days 0 (baseline), 1, and 3 since VEGF121/rGel treatment started. Dynamic PET-derived binding potential (BPND) and parametric maps were compared with tumor uptake (%ID/g) and the static PET image at 1 h after the tracer administration.ResultsThe growth of U87MG tumor was obviously delayed upon VEGF121/rGel treatment. A549 tumor was not responsive to the same treatment. BPND of treated U87MG tumors decreased significantly at day 1 (p < 0.05), and the difference was more significant at day 3 (p < 0.01), compared with the control group. However, the tracer uptake (%ID/g) derived from static images at 1-h time point did not show significant difference between the treated and control tumors until day 3. Little difference in tracer uptake (%ID/g) or BPND was found between treated and control A549 tumors. Considering the tracer retention in tumor and the slower clearance due to damaged tumor vasculature after treatment, BPND representing the actual specific binding portion appears to be more sensitive and accurate than the semiquantitative parameters (such as %ID/g) derived from static images to assess the early response of tumor to VDA treatment.ConclusionsQuantitative analysis based on dynamic PET with [(18)F]FPPRGD2 shows advantages in distinguishing effective from ineffective treatment during the course of VEGF121/rGel therapy at early stage and is therefore more sensitive in assessing therapy response than static PET.

| S-EPMC5218587 | biostudies-literature

Evaluation of tumor ischemia in response to an indole-based vascular disrupting agent using BLI and (19)F MRI.

Project description:Vascular disrupting agents (VDAs) have been proposed as an effective broad spectrum approach to cancer therapy, by inducing ischemia leading to hypoxia and cell death. A novel VDA (OXi8007) was recently reported to show rapid acute selective shutdown of tumor vasculature based on color-Doppler ultrasound. We have now expanded investigations to noninvasively assess perfusion and hypoxiation of orthotopic human MDA-MB-231/luc breast tumor xenografts following the administration of OXi8007 based on dynamic bioluminescence imaging (BLI) and magnetic resonance imaging (MRI). BLI showed significantly lower signal four hours after the administration of OXi8007, which was very similar to the response to combretastatin A-4P (CA4P), but the effect lasted considerably longer, with the BLI signal remaining depressed at 72 hrs. Meanwhile, control tumors exhibited minimal change. Oximetry used (19)F MRI of the reporter molecule hexafluorobenzene and FREDOM (Fluorocarbon Relaxometry using Echo Planar Imaging for Dynamic Oxygen Mapping) to assess pO2 distributions during air and oxygen breathing. pO2 decreased significantly upon the administration of OXi8007 during oxygen breathing (from 122 ± 64 to 34 ± 20 Torr), with further decrease upon switching the gas to air (pO2 = 17 ± 9 Torr). pO2 maps indicated intra-tumor heterogeneity in response to OXi8007, though ultimately all tumor regions became hypoxic. Both BLI and FREDOM showed the efficacy of OXi8007. The pO2 changes measured by FREDOM may be crucial for future study of combined therapy.

| S-EPMC4396009 | biostudies-literature

Monitoring tumor response to the vascular disrupting agent CKD-516 in a rabbit VX2 intramuscular tumor model using PET/MRI: Simultaneous evaluation of vascular and metabolic parameters.

Project description:To determine whether the CKD-516 produces a significant change in vascular and metabolic parameters in PET/MRI.With institutional Animal Care and Use Committee approval, 18 VX2 carcinoma tumors implanted in bilateral back muscles of 9 rabbits were evaluated. Serial PET/MRI were performed before, 4 hours after and 1-week after vascular disrupting agent, CKD-516 at a dose of 0.7 mg/kg (treated group, n = 10) or saline (control group, n = 8) administration. PET/MRI-derived parameters and their interval changes were compared between the treated and control group by using the linear mixed model. Each parameter within each group was also compared by using the linear mixed model.Changes of the volume transfer coefficient (Ktrans) and the initial area under the gadolinium concentration-time curve until 60 seconds (iAUC) in the treated group were significantly larger compared with those in the control group at 4-hour follow-up (mean, -39.91% vs. -6.04%, P = 0.018; and -49.71% vs. +6.23%, P = 0.013). Change of metabolic tumor volume (MTV) in the treated group was significantly smaller compared with that in the control group at 1-week follow-up (mean, +118.34% vs. +208.87%, P = 0.044). Serial measurements in the treated group revealed that Ktrans and iAUC decreased at 4-hour follow-up (P < 0.001) and partially recovered at 1-week follow-up (P = 0.001 and 0.024, respectively). MTV increased at a 4-hour follow-up (P = 0.038) and further increased at a 1-week follow-up (P < 0.001), while total lesion glycolysis (TLG) did not show a significant difference between the time points. SUVmax and SUVmean did not show significant interval changes between time points (P > 0.05).PET/MRI is able to monitor the changes of vascular and metabolic parameters at different time points simultaneously, and confirmed that vascular changes precede the metabolic changes by VDA, CKD-516.

| S-EPMC5811032 | biostudies-literature

Vascular disrupting agent in pancreatic and hepatic tumour allografts: observations of location-dependent efficacy by MRI, microangiography and histomorphology.

Project description:BackgroundTumours growing in organs of different vascular environment could exhibit diverse responses to vascular disrupting agent (VDA). This study was aimed to identify in vivo imaging biomarkers for evaluation of pancreatic and hepatic tumours and comparison of their responses to a VDA Combretastatin A4 Phosphate (CA4P) using multiparametric MRI.MethodsMale WAG/Rij rats were used for orthotopic pancreatic head tumour and hepatic tumour implantation; tumour growth was monitored by 3D isotropic MRI using a 3.0-T clinic scanner. Therapeutic intervention using CA4P was investigated by in vivo quantitative MRI measurements including T2/T1 relaxation mapping, diffusion kurtosis imaging and dynamic contrast-enhancement (DCE) imaging. Animals were scarified 10?h after CA4P treatment for ex vivo validation using microangiography and histomorphology.ResultsState-of-the-art clinical MRI protocols were successfully adapted for imaging small animal tumour with high reliability. One hour after CA4P injection, marked vascular shutdown was detected with DCE MRI in both pancreatic and hepatic tumours. However, 10?h later, therapeutic necrosis was limited in pancreatic tumours compared with that in hepatic tumours (P<0.01). Heterogeneous therapeutic changes were depicted in tumour lesions using pixel-wise Tofts model, which was generated from dynamic T1 mapping. In addition, tumour responses including haemorrhage, oedema and necrosis were detected using quantitative T2/T1 relaxation maps and diffusion kurtosis images, and were validated using histomorphology.ConclusionsUsing multiparametric imaging biomarkers, hepatic tumours were found to be significantly more responsive to CA4P than pancreatic tumours, which could be of reference for designing future clinical trials on this agent.

| S-EPMC5680470 | biostudies-literature

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

Project description: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.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.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).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.

| S-EPMC4720091 | biostudies-literature

Tumour biomechanical response to the vascular disrupting agent ZD6126 in vivo assessed by magnetic resonance elastography.

Project description:Magnetic resonance elastography (MRE) is an emerging imaging technique that affords non-invasive quantitative assessment and visualization of tissue mechanical properties in vivo.In this study, MRE was used to quantify (kPa) the absolute value of the complex shear modulus |G*|, elasticity Gd and viscosity Gl of SW620 human colorectal cancer xenografts before and 24 h after treatment with either 200 mg kg(-1) of the vascular disrupting agent ZD6126 (N-acetylcolchinol-O-phosphate) or vehicle control, and the data were compared with changes in water diffusivity measured by diffusion-weighted magnetic resonance imaging.A heterogeneous distribution of |G*|, Gd and Gl was observed pre-treatment with an intertumoral coefficient of variation of 13% for |G*|. There were no significant changes in the vehicle-treated cohort. In contrast, ZD6126 induced a significant decrease in the tumour-averaged |G*| (P<0.01), Gd (P<0.01) and Gl (P<0.05), and this was associated with histologically confirmed central necrosis. This reduction in tumour viscoelasticity occurred at a time when no significant change in tumour apparent diffusion coefficient (ADC) was observed.These data demonstrate that MRE can provide early imaging biomarkers for treatment-induced tumour necrosis.

| S-EPMC3974089 | biostudies-other

A phase I pharmacokinetic study of the vascular disrupting agent ombrabulin (AVE8062) and docetaxel in advanced solid tumours.

Project description:BackgroundThe vascular disrupting agent ombrabulin shows synergy with docetaxel in vivo. Recommended phase II doses were determined in a dose escalation study in advanced solid tumours.MethodsOmbrabulin (30-min infusion, day 1) followed by docetaxel (1-h infusion, day 2) every 3 weeks was explored. Ombrabulin was escalated from 11.5 to 42 mg m(-2) with 75 mg m(-2) docetaxel, then from 30 to 35 mg m(-2) with 100 mg m(-2) docetaxel. Recommended phase II dose cohorts were expanded.ResultsFifty-eight patients were treated. Recommended phase II doses were 35 mg m(-2) ombrabulin with 75 mg m(-2) docetaxel (35/75 mg m(-2); 13 patients) and 30 mg m(-2) ombrabulin with 100 mg m(-2) docetaxel (30/100 mg m(-2); 16 patients). Dose-limiting toxicities were grade 3 fatigue (two patients; 42/75, 35/100), grade 3 neutropaenic infection (25/75), grade 3 headache (42/75), grade 4 febrile neutropaenia (30/100), and grade 3 thrombosis (35/100). Toxicities were consistent with each agent; mild nausea/vomiting, asthaenia/fatigue, alopecia, and anaemia were common, as were neutropaenia and leukopaenia. Diarrhoea, nail disorders and neurological symptoms were frequent at 100 mg m(-2) docetaxel. Pharmacokinetic analyses did not show any relevant drug interactions. Ten patients had partial responses (seven at 30 mg m(-2) ombrabulin), eight lasting >3 months.ConclusionsSequential administration of ombrabulin with 75 or 100 mg m(-2) docetaxel every 3 weeks is feasible.

| S-EPMC4007230 | biostudies-literature

Vascular disrupting agent induced aggregation of gold nanoparticles for photothermally enhanced tumor vascular disruption.

Project description:Although vascular disrupting agents (VDAs) have been extensively implemented in current clinical tumor therapy, the notable adverse events caused by long-term dosing severely limit the therapeutic efficacy. To improve this therapy, we report a strategy for VDA-induced aggregation of gold nanoparticles to further destroy tumor vascular by photothermal effect. This strategy could effectively disrupt tumor vascular and cut off the nutrition supply after just one treatment. In the murine tumor model, this strategy results in notable tumor growth inhibition and gives rise to a 92.7% suppression of tumor growth. Besides, enhanced vascular damage could also prevent cancer cells from distant metastasis. Moreover, compared with clinical therapies, this strategy still exhibits preferable tumor suppression and metastasis inhibition ability. These results indicate that this strategy has great potential in tumor treatment and could effectively enhance tumor vascular damage and avoid the side effects caused by frequent administration.

| S-EPMC7274768 | biostudies-literature

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

Project description:We report a phase I pharmacological study of an oral formulation of CKD-516, a vascular-disrupting agent, in patients with refractory solid tumors. Twenty-seven patients (16 in the dose-escalation cohort and 11 in the expansion cohort) received a single daily dose (5-25 mg) of CKD-516 five days per week. Nausea (67%) and diarrhea (63%) were the most common treatment-related adverse events. The recommended phase II dose of oral CKD-516 was 20 mg/d (15 mg/d with a body surface area (BSA) <1.65 m2 ). Notably, S-516 half-lives in patients receiving 15-20 mg CKD-516/d significantly differed between patients with and without splenomegaly that is suggestive of portal hypertension associated with liver cirrhosis (6.1 vs 4.6 hours, respectively). Of 11 patients without splenomegaly who completed at least one cycle of a daily CKD-516 dose of either 15 or 20 mg, only one patient (9.1%) suffered from any dose-limiting toxicity. We conclude that a daily oral dose of 15 or 20 mg CKD-516 five days per week could be tolerable in patients without liver cirrhosis.

| S-EPMC7066534 | biostudies-literature

Enhanced antitumor efficacy of a vascular disrupting agent combined with an antiangiogenic in a rat liver tumor model evaluated by multiparametric MRI.

Project description:A key problem in solid tumor therapy is tumor regrowth from a residual viable rim after treatment with a vascular disrupting agent (VDA). As a potential solution, we studied a combined treatment of a VDA and antiangiogenic. This study was approved by the institutional ethical committee for the use and care of laboratory animals. Rats with implanted liver tumors were randomized into four treatment groups: 1) Zd6126 (Zd); 2) Thalidomide (Tha); 3) Zd in combination with Tha (ZdTha); and 4) controls. Multiparametric MRIs were performed and quantified before and after treatment. Circulating endothelial progenitor cells (EPCs) and plasma stromal cell-derived factor-1α (SDF-1α) were monitored. Tumor apoptosis, necrosis, and microvessels were verified by histopathology. A single use of Zd or Tha did not significantly delay tumor growth. The combined ZdTha showed enhanced antitumor efficacy due to synergistic effects; it induced a cumulative tumor apoptosis or necrosis, which resulted in significant delay in tumor growth and reduction in the viable tumor rim; it also reduced tumor vessel permeability; and it improved tumor hemodynamic indexes, most likely via a transient normalization of tumor vasculature induced by Tha. A stepwise linear regression analysis showed that the apparent diffusion coefficient was an independent predictor of tumor growth. We found no significant increases in Zd-induced circulating EPCs or plasma SDF-1α. ZdTha showed improved therapeutic efficacy in solid tumors compared to either agent alone. The therapeutic effects were successfully tracked in vivo with multiparametric MRI.

| S-EPMC3399789 | biostudies-literature

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