Combretastatin A-4 phosphate (CA4P) carboplatin and paclitaxel in patients with platinum-resistant ovarian cancer: Final phase II trial results.
Zweifel M., Jayson G., Reed N., Osborne R., Hassan B., Shreeves G., Poupard L., Walicke PA., Balkissoon J., Chaplin D., Rustin G.
5502 Background: CA4P is a vascular disrupting agent that in pre-clinical models can increase the efficacy of a variety of therapies. A dose escalation trial of CA4P given prior to carboplatin, paclitaxel or both showed the combination was well tolerated and responses were seen in several tumor types including 6/17 with relapsed ovarian cancer. The trial was therefore extended into a phase II trial in patients with platinum resistant ovarian cancer. METHODS: Patients with ovarian cancer that had relapsed and could start trial therapy within 6 months of their last platinum chemotherapy were given CA4P 63mg/m(2) 18-20 hours prior to paclitaxel 175mg/m(2) and carboplatin AUC 5 repeated 3 weekly. If > 2 responses were seen in first 18 patients 43 patients were to be treated to confirm response rate>19%. RESULTS: Five of the first 18 patients responded so the study was extended and closed after 44 patients were recruited, with full data available to date on 34. Weekly blood counts have demonstrated grade 3/4 neutropenia in 11 and thrombocytopenia in only 1 patient. Other grade > 2 toxicity seen in > 1 patient was fatigue, nausea / vomiting, pain, alopecia, rapidly reversible ataxia, diarrhoea, neuropathy and was little different to what would be expected with paclitaxel and carboplatin. Hypertension is the commonest CA4P related toxicity and was easily controlled by GTN, then prophylactic amlodipine. Responses according to GCIG criteria, have been seen in 11/34 (32%) patients with an additional unconfirmed PR. CONCLUSIONS: The addition of CA4P to paclitaxel and carboplatin is well tolerated and appears to produce a higher response rate in this patient population than if the chemotherapy was given without CA4P. A planned randomised trial will hopefully confirm this. [Table: see text].