I know BMS's involvement is more validation that I could muster. I know there have been many patients treated in PI, and the company feels it has shown safety in humans. But as for the drug's specificity, can anyone help me understand this abstract which suggests to me that the drug has the same effect on important normal tissue as it does on tumors? (ASCO 2000)
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Measurement of Tumour and Normal Tissue (NT) Perfusion by Positron Emission Tomography (PET) in the Evaluation of Antivascular Therapy: Results in the Phase I Study of Combretastatin A4 Phosphate (CA4P). Helen Anderson, Jeff Jap, Pat Price, CRC PET Oncology Group Hammersmith Hosp, London, UK.
Aim: To evaluate the timing, magnitude and dose related effects of CA4P on tumour and NT perfusion using quantitative H215O PET. Methods: CA4P is a novel antivascular agent which has been shown to reduce blood flow in animal tumours. 8 patients (pts) treated with CA4P in the Phase I trial have been evaluated with PET to date and accrual is ongoing. CA4P was delivered by a 10 minute weekly infusion x3 every 4 weeks for up to 6 cycles of treatment with intra-patient dose escalation. Tumour and NT perfusion were measured using dynamic H215O PET an established technique for the quantification of in vivo perfusion. NT and tumour blood volume were also measured using C15O and analysis is ongoing. Examinations were performed immediately before, 30 minutes and 24 hrs after the first infusion of each dose level of CA4P. Perfusion was measured as an absolute value and changes in perfusion from baseline were calculated as % change. Results: 11 examinations have been performed in 8 patients (4F, 4M), median age 43 yrs (range 25-59yrs). Pre-treatment tumour perfusion ranged from 0.1070.557 ml/min/ml (mean 0.352). Normal tissue perfusion was consistently higher: mean spleen flow 1.02 (range 0.521.28), kidney 1.38 (range 0.811.73). At a dose range of 5288mg/m2 a 30-60% reduction in tumour perfusion was seen in 4/5 pts at 30 minutes. In ¾ pts this resolved by 24 hrs. At lower doses (5-20mg/m2) there appeared no consistent pattern of change due to small numbers. NT perfusion reduction (up to 63% kidney and 58% spleen) was seen in doses above 40mg/m2 but no changes in serum creatinine were subsequently seen. Conclusion: CA4P reduces tumour perfusion acutely in the dose range 52-88mg/m2 and can reduce NT perfusion. Ongoing analyses of additional patients and blood volume changes may help determine the mechanism of action. This study has been conducted on behalf of the Cancer Research Campaign Phase I/II committee and supported by Oxigene and the CRC.
--Wilder |
