Dose-finding study of valspodar (PSC 833) with daunorubicin and cytarabine to reverse multidrug resistance in elderly patients with previously untreated acute myeloid leukemia.

INTRODUCTION: This trial was designed to determine the maximum tolerated dose of intravenous daunorubicin (DNR) in combination with valspodar and to test the feasibility of P-glycoprotein modulation using valspodar in elderly patients with previously untreated acute myelogenous leukemia receiving standard induction chemotherapy. METHODS: Patients > or =60 years of age with previously untreated AML received valspodar (10 mg/kg/24 h by continuous intravenous infusion [CIV] on days 1-4 with a 2-mg/kg loading dose on day 1) in conjunction with two cycles of induction chemotherapy consisting of cytarabine (200 mg/m(2) CIV on days 1-7), and DNR (35 mg/m(2) [cohort 1] or 45 mg/m(2) [cohort 2] on days 1-3, intravenous bolus). Patients were assessed for dose-limiting toxicities (DLT), response rate, event-free and overall survival, and pharmacokinetics of valspodar and DNR. RESULTS: Valspodar was well tolerated at the lower DNR dose level (ie, 35 mg/m(2)) resulting in a 21% rate of DLT and only three toxic deaths. Treatment-related mortality was unacceptably high at the 45 mg/m(2) DNR dose level. The complete response rate was 49% overall and similar in both cohorts. The median overall survival of patients was 333 days in cohort 1 compared to 98 days in cohort 2. At baseline, 70% of assessable patients were P-glycoprotein positive. CONCLUSION: Substantial inhibition of P-glycoprotein activity can be achieved in this patient population at clinically tolerable doses of valspodar and DNR. The maximum tolerated dose of DNR was established as 35 mg/m(2). This regimen is being further evaluated in phase III trials.

The pharmaceutical industry and oncology in central and eastern Europe.

Major opportunities exist for patients, investigators and the pharmaceutical industry in oncology drug development in Central and Eastern Europe. Novel therapeutics may be offered for investigational use in selected centres capable of adherence to Good Clinical Practice (GCP). Requirements for participation in oncology clinical trials include the availability of experienced qualified investigators highly motivated to conform with the principles of GCP (International Harmonization (ICH) guidelines); availability of appropriate Institutional Review Board for Human Subjects (IRB), access to appropriate patient populations, access to individual patient data, acceptance of possible audit by sponsoring companies and the Food and Drug Administration (FDA), and a willingness to participate in the generation of new knowledge. Patients gain through access to novel therapeutics. We have had success in performing clinical trials to international standards in Central and Eastern Europe. This experience will be described.

Opioid mydriasis: cross-tolerance between morphine and enkephalins.

The occurrence of cross-tolerance between morphine and met-enkephalin, and between morphine and DADL (D-Ala-D-Leu-enkephalin) in causing mydriasis in mice was studied. Morphine-tolerant mice treated with met-enkephalin or DADL intracerebroventricularly (ICV) showed marked reduction of the pupillary effect of the endopioids. Maximal mydriasis in tolerant animals was only about 30% for met-enkephalin and 50% for DADL, compared to levels in nontolerant animals. These results are among the first to demonstrate cross-tolerance between morphine and enkephalins in intact animals and may suggest involvement of multiple opiate receptor systems in producing mydriasis.