Anne Tompkins

Phase I trial of continuous infusion flavopiridol, a novel cyclin-dependent kinase inhibitor, in patients with refractory neoplasms.

PURPOSE We conducted a phase I trial of the cyclin-dependent kinase inhibitor, flavopiridol (National Service Center [NSC] 649890), to determine the maximum-tolerated dose (MTD), toxicity profile, and pharmacology of flavopiridol given as a 72-hour infusion every 2 weeks. PATIENTS AND METHODS Seventy-six patients with refractory malignancies with prior disease progression were treated with flavopiridol, with first-cycle pharmacokinetic sampling. RESULTS Forty-nine patients defined our first MTD, 50 mg/m2/d x 3 with dose-limiting toxicity (DLT) of secretory diarrhea at 62.5 mg/kg/d x 3. Subsequent patients received antidiarrheal prophylaxis (ADP) to define a second MTD, 78 mg/m2/d x 3 with DLT of hypotension at 98 mg/m2/d x 3. Other toxicities included a proinflammatory syndrome with alterations in acute-phase reactants, particularly at doses >50 mg/ m2/d x 3, which in some patients prevented chronic therapy every 2 weeks. In some patients, ADP was not successful, requiring dose-deescalation. Although approximately 70% of patients displayed predictable flavopiridol pharmacology, we observed unexpected interpatient variability and postinfusion peaks in approximately 30% of cases. At the two MTDs, we achieved a mean plasma flavopiridol concentration of 271 nM (50 mg/m2/d x 3) and 344 nM (78 mg/m2/d x 3), respectively. One partial response in a patient with renal cancer and minor responses (n=3) in patients with non-Hodgkins lymphoma, colon, and renal cancer occurred. CONCLUSION The MTD of infusional flavopiridol is 50 mg/m2/d x 3 with dose-limiting secretory diarrhea at 62.5 mg/m2/d x 3. With ADP, 78 mg/m2/d x 3 was the MTD, with dose-limiting hypotension at 98 mg/m2/d x 3. Based on chronic tolerability, 50 mg/m2/d x 3 is the recommended phase II dose without ADP. Antitumor effect was observed in certain patients with renal, prostate, and colon cancer, and non-Hodgkins lymphoma. Concentrations of flavopiridol (200 to 400 nM) needed for cyclin-dependent kinase inhibition in preclinical models were achieved safely.

A phase II study of 5-aza-2'deoxycytidine (decitabine) in hormone independent metastatic (D2) prostate cancer.

Aims and Background Decitabine (5-aza-2′-deoxycytidine) is an S-phase-specific pyrimidine analog with hypomethylation properties. In laboratory models of prostate cancer (PC-3 and DU-145), decitabine induces cellular differentiation and enhanced expression of genes involved in tumor suppression, immunogenicity, and programmed cell death. Methods We conducted a phase II study of decitabine in 14 men with progressive, metastatic prostate cancer recurrent after total androgen blockade and flutamide withdrawal. Decitabine was administered at a dose of 75 mg/m2/dose IV as a 1 hour infusion every 8 hours for three doses. Cycles of therapy were repeated every 5 to 8 weeks to allow for resolution of toxicity. Results Two of 12 patients evaluable for response had stable disease with a time to progression of more than 10 weeks. This activity was seen in 2 of 3 African-American patients. Toxicity was similar to previously reported experience. No significant changes in urinary concentrations of the angiogenic factor bFGF, a potential biomarker of tumor activity, were identified over time in 7 unselected patients with progressive disease. Conclusions We conclude that decitabine is a well tolerated regimen with modest clinical activity against hormone-independent prostate cancer. Further investigations in patients of African-American origin may be warranted.

Phase I study of phenylacetate administered twice daily to patients with cancer

Background. The growth‐inhibiting and differentiating effects of sodium phenylacetate against hematopoietic and solid tumor cell lines has aroused clinical interest in its use as an anticancer drug. In an earlier Phase I trial of phenylacetate aimed at maintaining serum drug concentrations in the range that proved active in vitro (>250 μg/ml) for 2 consecutive weeks, infusion rates approached the maximum velocity of drug elimination and commonly resulted in drug accumulation and reversible dose‐limiting neurologic toxicity. In this study, the authors described the nonlinear pharmacokinetics, metabolism, toxicity, and clinical activity of phenylacetate.

Disposition of phenylbutyrate and its metabolites, phenylacetate and phenylacetylglutamine

Phenylacetate, an inducer of tumor cytostasis and differentiation, shows promise as a relatively nontoxic antineoplastic agent. Phenylacetate, however, has an unpleasant odor that might limit patient acceptability. Phenylbutyrate, an odorless compound that also has activity in tumor models, is known to undergo rapid conversion to phenylacetate by beta‐oxidation in vivo. This phase I study examined the pharmacokinetics of phenylbutyrate and characterized the disposition of the two metabolites, phenylacetate and phenylacetylglutamine. Fourteen patients with cancer (aged 51.8 ± 13.8 years) received a 30‐minute infusion of phenylbutyrate at 3 dose levels (600, 1200, and 2000 mg/m2). Serial blood samples and 24‐hour urine collections were obtained. Samples were assayed by high‐performance liquid chromatography. A model to simultaneously describe the pharmacokinetics of all three compounds was developed using ADAPT II. Data were modeled as molar equivalents. The model fit the data well as shown by mean (±SD) coefficients of determination (r2) for phenylbutyrate, phenylacetate, and phenylacetylglutamine, which were 0.96 ± 0.07, 0.88 ± 0.10, and 0.92 ± 0.06, respectively. The intrapatient coefficient of variation percentage (CV%) around the parameter estimates were small (range 7.2–33.5%). Phenylbutyrate achieved peak concentrations in the range of in vitro tumor activity (500–2000 μmol/L) and exhibited saturable elimination (Km = 34.1 ± 18.1 μg/mL and Vmax = 18.1 ± 18 mg/h/kg). Metabolism was rapid; the times to maximum concentration for phenylacetate and phenylacetylglutamine were 1 and 2 hours, respectively. The conversion of phenylbutyrate to phenylacetate was extensive (80 ± 12.6%), but serum concentrations of phenylacetate were low owing to rapid, subsequent conversion to phenylacetylglutamine. The ratio of phenylbutyrate AUC to phenylacetate AUC was 2.66. Thus, phenylbutyrate may not be a prodrug for phenylacetate and should be pursued as an independent antitumor agent.

Phase II trial of suramin, leuprolide, and flutamide in previously untreated metastatic prostate cancer.

PURPOSE To assess the efficacy and toxicity of suramin, hydrocortisone, leuprolide, and flutamide in previously untreated metastatic prostate cancer. PATIENTS AND METHODS Patients with stage D2 and poor-prognosis stage D1 prostate cancer were given suramin on a pharmacokinetically derived dosing schedule to maintain suramin concentrations between 175 and 300 micrograms/mL. Additionally, all patients received flutamide 250 mg orally three times daily, initiated on day 1 and continued until disease progression; depot leuprolide 7.5 mg intramuscularly begun on day 5 and repeated every 4 weeks indefinitely; and replacement doses of hydrocortisone. RESULTS Fifty patients were entered onto the study: 48 with stage D2 and two with stage D1 disease. The median age was 59 years (range, 42 to 79) and 31 patients had a Karnofsky performance status (KPS) of 100%. Forty-five patients had bone metastases and 25 had measurable soft tissue disease. Forty-one (82%) had severe disease. The overall response rate in 49 assessable patients was three complete responses (CRs) and 30 partial responses (PRs) for an overall response rate of 67%. Eighteen patients have died. The median survival time has not been reached, with a median potential follow-up duration of 44 months. Grade 3 to 4 toxicity was seen in 38% of patients and was predominantly hematologic and reversible. CONCLUSION The high response rate and prolonged survival in a poor-prognosis group of patients with metastatic prostate cancer warrant a phase III randomized comparison of this regimen versus hormonal therapy alone. Toxicity was moderate and reversible.

Flutamide withdrawal and concomitant initiation of aminoglutethimide in patients with hormone refractory prostate cancer

Total androgen deprivation is by many clinicians considered to be the optimal therapeutic regimen for hormone sensitive prostate cancer (1-2). Complete androgen blockade is usually accomplished with either orchiectomy or an LHRH agonist such as leuprolide, that inhibits testicular androgen production, together with an antiandrogen such as flutamide. Flutamide is a pure antiandrogenic compound that prevents the androgen receptor from binding testosterone and dihydrotestosterone (DHT) without exhibiting hormonal acivity of its own (3, 4).

Data Management in Clinical Trials

Publisher Summary Data management includes the entire spectrum from data collection and entry to data analysis and reporting. The data collected in a clinical trial constitute an accounting of the trial. Rules and guidelines that govern research include the Code of Federal Regulations, the Good Clinical Practices (GCPs) guidelines from the International Conference on Harmonisation, state laws, sponsor standard operating procedures (SOPs), and institutional SOPs. The GCPs are an international ethical and scientific quality standard for clinical trial conduct. A trial conducted under good clinical practices is the basis for demonstrating that the trial was conducted according to protocol. Even as automated systems are employed to facilitate clinical trial data management, the central themes remain: the trial conducted according to good clinical practices, carrying out the study according to protocol, and treatment and assessment of the participant according to protocol. These issues should always be raised and affirmed to assure the integrity of the research and the protection of the safety of the participant. Plans for data management should be set up early during the development phase of a clinical trial. Included in the plan are the appropriate mix of research personnel and resources such as staff time, workspace, computer equipment, and secure storage facilities for both paper and electronic equipment.

Phenylacetate Pharmacokinetics Based on Iterative Two‐Stage Population Analysis

Study Objective. To determine the population pharmacokinetics of phenylacetate using iterative two‐stage analysis implemented with ADAPT II software.