Phase I, pharmacokinetic and pharmacodynamic evaluation of CYT997, an orally-bioavailable cytotoxic and vascular-disrupting agent.

PURPOSE: CYT997 is a novel microtubule inhibitor and vascular disrupting agent. This phase I trial examined the safety, tolerability, pharmacokinetics and vascular-disrupting effects of orally-administered CYT997. EXPERIMENTAL DESIGN: We performed a phase I accelerated dose-escalation study of CYT997 given orally once every 2 to 3 weeks in patients with advanced solid tumours. Vascular disruption was assessed by measurement of plasma von Willebrand factor (vWF) levels and dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI). RESULTS: A total of 56 doses were administered to 21 patients over 8 dose levels (15-164 mg/m(2)). Grade 3 fatigue and grade 3 hypoxia were dose limiting. Oral bioavailability was observed with approximate linear pharmacokinetics over the 11-fold dose range. At doses of 84 mg/m(2) and above, plasma vWF levels increased above baseline and DCE-MRI scans showed reductions in tumour K(trans) in some patients. CONCLUSIONS: CYT997 is orally bioavailable. The 118 mg/m(2) dose level should be used to guide dosing in future studies.

Carboplatin and etoposide combined with bevacizumab for the treatment of recurrent glioblastoma multiforme.

Relapsed glioblastoma multiforme (GBM) responds poorly to standard therapies. Vascular endothelial growth factor (VEGF) is implicated in the development of GBM and the anti-VEGF monoclonal antibody bevacizumab has shown early clinical promise against malignant glioma. We treated six patients with recurrent GBM using bevacizumab combined with carboplatin and etoposide chemotherapy (ACE regimen). Toxicity was that expected for carboplatin and etoposide alone, except for an ischemic stroke in one patient. We observed partial responses in five patients and one responding patient developed extensive tumour necrosis after 2 cycles of treatment. Median progression-free and overall survival was 19 and 29.9weeks, respectively. Four responding patients developed recurrence, which was characterized by markedly less peri-tumoral edema, mass effect and necrosis compared with tumours at baseline. Two patients developed local extracranial extension. In conclusion, ACE was active in recurrent GBM and was mostly well tolerated.

Ranked importance of outcomes of first-line versus repeated chemotherapy among ovarian cancer patients.

PURPOSE: To examine the importance of possible outcomes of first-line versus repeated chemotherapy to ovarian cancer patients and to compare doctors' treatment intentions with patients' beliefs about cure. METHODS: Women with newly diagnosed (74) or relapsed (48) ovarian cancer were prospectively followed over 2 years. The level of importance they ascribed to four chemotherapy outcomes and their beliefs about cure were assessed. Their doctors independently specified intent of successive treatments. RESULTS: Approximately half (54%) of newly diagnosed ovarian cancer patients (65% with residual disease >2 cm and 49% with no or < or =2 cm residual disease) ranked 'tumour shrinkage (or decrease in blood levels of CA125)' as 'most important' during first-line chemotherapy. Approximately two thirds (65-70%) of all women whose disease had relapsed also ranked 'tumour shrinkage' as 'most important' during repeated chemotherapy. Few women (<8%) rated symptom relief or absence of side-effects as most important. While both patients' and doctors' belief about cure decreased over successive treatments, patients grew more optimistic relative to doctors over time. Women's reports of advice by doctors about cure were consistent with doctors' stated intent for repeat chemotherapy. However, discordance between doctors' actual treatment intent and patients' beliefs about cure increased from 24% at first-line to 83% by fourth-line chemotherapy. CONCLUSIONS: Women prioritise tumour response as the most important outcome of chemotherapy for ovarian cancer. This priority predominates in women with residual and relapsed disease despite declining likelihood of cure. Women may still hope for a cure while acknowledging their doctor's advice that their disease is incurable.