PHASE I-II STUDY OF VINBLASTINE AND ORAL CYCLOSPORINE-A IN METASTATICRENAL-CELL CARCINOMA

A phase I-II clinical trial was conducted to determine the maximum-tol erated dose (MTD) of oral cyclosporine (CsA) and vinblastine in patien ts with metastatic renal cell cancer (RCC) as well as to estimate the response rate. Sixteen patients received a 5 mg/kg oral loading dose o f CsA followed by 3 days of CsA in 4 divided daily doses escalating fr om 10 mg/ kg per day up to 17 mg/kg per day. Vinblastine (Vbl) was adm inistered as an intravenous bolus on the morning of the 3rd day with d ose escalation from 6 to 10 mg/m(2). Cycles were repeated every 4 week s until tumor progression. Forty-nine cycles of CsA with vinblastine w ere administered. The maximum tolerated dose of Vbl was 10 mg/m(2), wi th neutropenia as the dose-limiting toxicity resulting in one death. C sA could not be escalated above 17 mg/kg per day because of nausea and vomiting. Other toxicities included constipation (100%), malaise (100 %), temporary increase in pain (36%), and one seizure that may have be en drug-related. There were no clinically significant changes in renal function or serum bilirubin. Mean peak whole-blood CsA level at the h ighest CsA dose level was 919 ng/ml (range: 414-1,827) with a trough p rior to Vbl injection of 451 ng/ml (range: 128-1,229). There were no t umor responses. The combination of oral CsA and Vbl is not nephrotoxic but is poorly tolerated. In most patients optimal blood levels of CsA for reversal of MDR cannot be reliably achieved, and vinblastine dose intensity must be compromised because of the significant toxicity of this regimen.