Phase I trial of CYT997, a novel cytotoxic and vascular-disrupting agent

Abstract

Background: CYT997 is a novel microtubule inhibitor and vascular-disrupting agent with marked preclinical anti-tumour activity.

Methods: This phase I dose-escalation study assessed the safety, tolerability, pharmacokinetics and pharmacodynamics of CYT997 administered by continuous intravenous infusion over 24 h every 3 weeks to patients with advanced solid tumours.

Results: Thirty-one patients received CYT997 over 12 dose levels (7-358 mg m(-2)). Doses up to 202 mg m(-2) were well tolerated. Dose-limiting toxicities were observed at 269 and 358 mg m(-2), consisting of grade 3 prolonged corrected QT interval in two patients and grade 3 hypoxia and grade 4 dyspnea in one patient. All toxicities were reversible. The pharmacokinetics of CYT997 were linear over the entire dose range. Dynamic contrast-enhanced magnetic resonance imaging scans showed significant changes in tumour K(trans) values consistent with vascular disruption in 7 out of 11 evaluable patients treated at CYT997 doses of >or=65 mg m(-2). Moreover, plasma levels of von Willebrand factor and caspase-cleaved cytokeratin-18 increased post-treatment at higher dose levels. Among 22 patients evaluable for response, 18 achieved stable disease for >2 cycles.

Conclusions: CYT997 was well tolerated at doses that were associated with pharmacodynamic evidence of vascular disruption in tumours.

Figure 1

Pharmacokinetic profile of CYT997 given by continuous 24-h i.v. infusion. (A) Area under the plasma concentration–time curve (AUC_0−t), and (B) plasma concentration at steady state (C_ss), vs CYT997 dose level. (C) Mean plasma concentration of CYT997 plotted against time from the infusion start for the 269 mg m⁻² dose level (n=4); error bars indicate s.d.

Figure 2

Vertical scatter plots of (A) von Willebrand factor (vWF) antigen levels and (B) caspase-cleaved cytokeratin-18 (CK-18) levels in plasma at 24 h after commencing the initial CYT997 infusion, grouped by CYT997 dose level. Values are expressed as a percentage of baseline values for each patient and mean values for each dose level are indicated by horizontal bars. For caspase-cleaved CK-18 levels, each data point represents the mean of duplicate assays. Note that there was only one patient per dose level at four of the dose levels (86, 114, 152 and 202 mg m⁻²).

Figure 3

Tumour K^trans maps derived from DCE-MRI scans of patients 20 (A, C) and 26 (B, D). Patient 20 received 114 mg m⁻² of CYT997 and the lesion shown is a liver metastasis of non-small cell lung cancer. Patient 26 received 269 mg m⁻² and images show a pelvic nodal metastasis of ovarian carcinoma. Results at baseline (A, B) and 6 days following CYT997 administration (C, D) are shown. Maps are colour coded, and the scale (shown at right) extends from a maximum K^trans of 0.02 min⁻¹ (yellow end) to zero (blue end). Histograms indicating the mean change in K^trans for each decile of voxels at 6 days following CYT997 treatment are also shown for patients 20 and 26 (E and F, respectively). The bars are arranged so that the decile with the lowest K^trans values at baseline is on the left of the histogram and the decile with the highest is on the right. Negative values indicate a fall in K^trans after study drug, compared with baseline. Asterisks indicate statistical significance: ^*P<0.05, ^**P<0.0002.

Figure 4

Correlation between the whole-tumour median K^trans value at baseline and the maximum decrease in whole-tumour median K^trans observed following CYT997 treatment. Only data from patients with a fall in median K^trans at one or both post-treatment time points are shown.