Two more:
Dynamic Gadolinium-Enhanced MRI of Tumors: Effects of CA4P on Tumor Blood Flow.
Mark A. Rosen, Sarah Englander, James Stevenson, Peter B. O'Dwyer, Mitchell Schnall, University of Pennsylvania, Philadelphia, PA.
Combretastatin A4 phosphate (CA4P) is an anti-tubulin agent known to target proliferating endothelial cells. Vascular shutdown is the proposed mechanism of antitumor activity. We investigated the ability of dynamic gadolinium-enhanced MRI (DE-MRI) to delineate changes in tumor perfusion within humans, and the applicability of quantitative kinetic analysis of DE-MRI data. Ten patients receiving CA4P as a daily x 5 10 minute IV infusion repeated every 21 days were studied. Patients were imaged with DE-MRI prior to initiation of therapy, and 5-6 hours following completion of the day 5 dose. DE-MRI results were analyzed quantitatively, and gadolinium concentration was fit to a three-compartment model to allow for extraction of kinetic parameters relating to tumor blood flow (Ktr) and volume fraction of vascular-accessible interstitial space (Ve). In three of the ten patients (all with small lung metastases), quantitative analysis could not be performed secondary to excessive respiratory or cardiac artifacts. Of the remaining seven patients, values of Ktr ranged from 0.42 to 3.32 min-1 pretreatment, and from 0.29 to 2.16 min-1 post-CA4P. Five of the seven patients demonstrated a decrease in Ktr following therapy (mean change –0.78 min-1, range –2.35 to +0.41), although the differences did not reach statistical significance (P=0.12). For two of the patients, Ktr fell by greater than 50%. One of these patients demonstrated macroscopically visible areas of devascularization on the post-CA4P MRI. Values for Ve ranged from 0.22 to 0.79 pretreatment, and from 0.16 to 0.66 post-CA4P. Six of seven patients demonstrated decreases in Ve following CA4P (mean change –0.15, range –0.37 to +0.01, P=0.006). There was no statistically significant change in Ktr or Ve in muscle for the same seven patients (P=0.54 and P=0.71, respectively). DE-MRI is a robust method for evaluating alterations in tumor blood flow in patients undergoing anti-vascular chemotherapy, and can depict global and regional vascular responses to therapy. (Trial supported by OXiGENE, INC., Boston, MA)
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Phase 1 Study of Weekly Intravenous Combretastatin A4 Phophate (CA4P): Pharmacokinetics and Toxicity.
Gordon J.S. Rustin, P Price, M Stratford, S Galbraith, H Anderson, L Folkes, A Robbins, L Senna, Mount Vernon Hospital, Middlesex, UK; CRC PET Oncology Group, Hammersmith Hospital, London, UK; Gray Laboratory, Northwood, UK; Cancer Research Campaign, London, UK.
CA4P is a novel tubulin binding agent that has been shown to rapidly reduce blood flow in animal and human tumours. The drug was delivered by a 10min weekly infusion x3 followed by a week gap, with intra-patient dose escalation until 2 instances of ³grade II toxicity occurred. Dose escalation was by doubling until grade II toxicity was seen, then by 1.3. The starting dose was 5mg/m2. To date 32 patients have received 163 infusions. CA4P was rapidly converted to the active CA4, which was further metabolised to the glucuronide; 15min after the end of infusion, the latter was the dominant species in the plasma. CA4 AUC increased from 0.189 at 5mg/m2 to 3.29µmol.h/L at 114mg/m2, while peak concentrations (Cmax) increased from 0.407 to 4.46µM over the same dose range. The mean CA4 AUC and Cmax in 5 patients at 68mg/m2 were 2.05µmol.h/L and 1.66µM respectively, compared to 5.8µmol.h/L and 9.8µM at 25mg/kg (the lowest effective dose) in the mouse. The only possibly drug-related toxicity up to 40mg/m2 included tumour pain and lymphopenia. Dose-limiting toxicity was reversible ataxia at 114mg/m2 and vasovagal syncope and motor neuropathy at 88mg/m2. Other drug related toxicities ³grade II were pain, 10 patients (6 tumour site), fatigue 7, visual disturbance 3, hypotension 2, hypertension 3, dyspnoea 2, nausea 1, vomiting 2, headache 1, and fatal ischaemia in previously irradiated bowel 1. One patient at 68 mg/m2, had a partial response in liver metastases of adrenocortical carcinoma after 12 infusions not maintained after a gap. CA4P was well tolerated in 11/13 patients at 52 or 68 mg/m2, and tumour blood flow reduction is reproducibly seen at these doses. This study has been conducted on behalf of The Cancer Research Campaign (CRC) Phase I/II Committee and supported by OXiGENE Inc and the National Lottery Charities Board. |
