A dose finding and pharmacokinetic study of the novel isoflavanoid phenoxodiol in patients with refractory malignancies. Year: 2003 Abstract No: 886 Category: Other Novel Agents T. E. Hutson, D. Plavney, T. Mekhail, R. Dreicer, G. T. Budd, D. Peereboom, T. Olencki, G. Kelly, R. Ganapathi, R. M. Bukowski; The Cleveland Clinic Foundation, Cleveland, OH; Novogen Pty Ltd, Sydney, Australia Abstract: Phenoxodiol, a naturally occurring isoflavanoid, is a cell-cycle active agent causing G1/M arrest with broad anti-tumor activity and minimal toxicity in animal models. Proposed mechanisms include modulation of signal transduction thru down-regulation of sphingosine kinase, inhibition of the anti-apoptotic proteins c-FLIP and XIAP, and up-regulation of the pro-apoptotic protein Bax. Objective: Phase I trial of phenoxodiol given by constant IV infusion in patients (pts) with refractory solid tumors to determine toxicity, maximal tolerable dose (MTD), pharmacokinetics (PK), and preliminary efficacy. Methods: Cohorts of 3 pts were treated with escalating doses of phenoxodiol (I-0.65, II-1.3, III-2.2, IV-3.3, V-20.0, VI-27.0 mg/kg/day) given by IV infusion continuously for 7 days in 2 week cycles until MTD or progression. Serum for PK obtained during cycle one (Day 1 at onset, 5, 10 and 30 mins, and 1, 2, 4 and 8 hours; Days 2, 3, 6, 8, 10 and 14) in all pts. Results: 19 pts (11 men; 8 women) were accrued at dose levels I (n=3), II (n=3), III (n=3), IV (n=3), V (n=4) and VI (n=3) with a variety of tumor types (Colorectal-5; Melanoma-3; Urothelial-4; Other-7) without dose limiting toxicity. All pts had received prior systemic therapy. Pts received a median of 3 cycles of treatment (range 1-13). Toxicity has included grade 3 AST (n=1; dose level 3), grade 3 GGT (n=1; dose level 4), and grade 2 fatigue (n=1; dose level 2 and n=2; dose level 3). There were no responses, however 10 pts had stable disease > 4 weeks in duration. Two pts (thymic CA -dose level 3 and RCC -dose level 2) received ³ 12 cycles. The mean AUC0-8 (standard error) for free and bound phenoxodiol were 67.5 (± 1.40), 129.3 (±19.6), 206.5 (± 33.6), 213.8 (± 51.4), 2529.3 (± 251.9), 3384.8 (± 479.3); and 2856.4 (± 525.0), 5524.0 (± 657.6), 10433.9 (± 789.3), 12272.8 (± 2246.7), 84883.3 (± 9436.1) and 145650.4 (± 5630.3) mg/ml·hr at dose levels I - VI respectively. Conclusion: Continuous IV administration of phenoxodiol is possible with minimal toxicity. Several pts had stable disease suggesting activity in this previously treated pt population. Further studies are planned, including a phase II trial in RCC. Remember we are NOT Doctors and have NO medical training. This site is like an Encylopedia - there are many pages, many links on many topics. Support our work with any size DONATION - see left side of any page - for how to donate. You can help raise awareness of CAM.